U.S. patent application number 13/376760 was filed with the patent office on 2012-07-05 for triazine derivatives and their therapeutical applications.
This patent application is currently assigned to CALIFORNIA CAPITAL EQUITY, LLC. Invention is credited to Neil Desai, David Ho, Laxman Nallan, Tulay Polat, Chunlin Tao, Qinwei Wang.
Application Number | 20120172361 13/376760 |
Document ID | / |
Family ID | 43309177 |
Filed Date | 2012-07-05 |
United States Patent
Application |
20120172361 |
Kind Code |
A1 |
Tao; Chunlin ; et
al. |
July 5, 2012 |
TRIAZINE DERIVATIVES AND THEIR THERAPEUTICAL APPLICATIONS
Abstract
Compounds of the formula (I) and formula (II) and
pharmaceutically acceptable salts thereof. ##STR00001##
Inventors: |
Tao; Chunlin; (Los Angeles,
CA) ; Wang; Qinwei; (Alhambra, CA) ; Polat;
Tulay; (Los Angeles, CA) ; Nallan; Laxman;
(Alhambra, CA) ; Ho; David; (Monterey Park,
CA) ; Desai; Neil; (Los Angeles, CA) |
Assignee: |
CALIFORNIA CAPITAL EQUITY,
LLC
Los Angeles
CA
|
Family ID: |
43309177 |
Appl. No.: |
13/376760 |
Filed: |
June 7, 2010 |
PCT Filed: |
June 7, 2010 |
PCT NO: |
PCT/US10/37614 |
371 Date: |
March 26, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61185056 |
Jun 8, 2009 |
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Current U.S.
Class: |
514/236.2 ;
514/241; 514/245; 544/113; 544/209; 544/212; 544/218 |
Current CPC
Class: |
C07D 401/14 20130101;
A61P 35/00 20180101; C07D 417/04 20130101; A61P 29/00 20180101;
A61P 35/02 20180101; C07D 413/12 20130101; C07D 417/14 20130101;
A61P 7/10 20180101; A61P 9/04 20180101; A61P 9/10 20180101; A61P
11/00 20180101; A61P 43/00 20180101; A61P 17/02 20180101; A61P 9/00
20180101; C07D 251/28 20130101; C07D 401/12 20130101; A61P 27/02
20180101; C07D 251/38 20130101; A61P 37/06 20180101; A61P 19/02
20180101; C07D 403/12 20130101 |
Class at
Publication: |
514/236.2 ;
544/209; 514/245; 544/212; 544/218; 514/241; 544/113 |
International
Class: |
A61K 31/53 20060101
A61K031/53; C07D 403/12 20060101 C07D403/12; C07D 251/38 20060101
C07D251/38; C07D 413/14 20060101 C07D413/14; A61K 31/5377 20060101
A61K031/5377; A61P 11/00 20060101 A61P011/00; A61P 9/04 20060101
A61P009/04; A61P 9/10 20060101 A61P009/10; A61P 19/02 20060101
A61P019/02; A61P 29/00 20060101 A61P029/00; A61P 37/06 20060101
A61P037/06; A61P 17/02 20060101 A61P017/02; C07D 403/14 20060101
C07D403/14; A61P 35/00 20060101 A61P035/00 |
Claims
1. A compound of the formula (I) ##STR00232## or a pharmaceutically
acceptable salt thereof, wherein: W and Y are independently
selected from S, O, NR.sub.4, CR.sub.4 or CR.sub.1; R.sub.4 is
independently selected from hydrogen or an optionally substituted
C.sub.1-4 aliphatic group. R.sub.1 represents hydrogen, halogen,
hydroxy, amino, cyano, alkyl, cycloalkyl, alkenyl, alkynyl,
alkylthio, aryl, arylalkyl, heterocyclic, heteroaryl,
heterocycloalkyl, alkylsulfonyl, alkoxycarbonyl and alkylcarbonyl.
R.sub.2 is selected from: (i) amino, alkyl amino, aryl amino,
heteroaryl amino; (ii) C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl; (iii) aryl, heterocyclic,
heteroaryl; and (iv) groups of the formula (Ia): ##STR00233##
wherein: R.sub.5 represents hydrogen, C.sub.1-C.sub.1 alkyl, oxo; X
is CH, when R.sub.6 is hydrogen; or X--R.sub.6 is O; or X is N,
R.sub.6 represents groups of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10
aryl or heteroaryl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.2-C.sub.6 alkanoyloxy, mono- and di-(C.sub.3-C.sub.8
cycloalkyl)aminoC.sub.0-C.sub.4alkyl, (4- to 7-membered
heterocycle)C.sub.0-C.sub.4alkyl, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6 alkyl)sulfonamido, and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl, each of which is
substituted with from 0 to 4 substituents independently chosen from
halogen, hydroxy, cyano, amino, --COOH and oxo; R.sub.3 is selected
from: (i) C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl; (ii) heterocyclic, (iii) K--Ar; Ar
represents heteroaryl or aryl, each of which is substituted with
from 0 to 4 substituents independently chosen from: (1) halogen,
hydroxy, amino, amide, cyano, --COOH, --SO.sub.2NH.sub.2, oxo,
nitro and alkoxycarbonyl; and (2) C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.10 cycloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkanoyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, mono- and
di-(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6alkyl)sulfonamido and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl; phenylC.sub.0-C.sub.4alkyl
and (4- to 7-membered heterocycle)-(C.sub.0-C.sub.4alkyl, each of
which is substituted with from 0 to 4 secondary substituents
independently chosen from halogen, hydroxy, cyano, oxo, imino,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and
C.sub.1-C.sub.4haloalkyl. K is selected from i) absence; ii) O, S,
SO, SO.sub.2; iii) (CH.sub.2).sub.m=0-3, --O(CH.sub.2).sub.p,
p=1-3, --S(CH.sub.2).sub.p, p=1-3, --N(CH.sub.2).sub.p, p=1-3,
--(CH.sub.2).sub.pO, p=1-3; iv) NR.sub.7 R.sub.7 represents
hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl,
arylalkyl.
2. A process for making compound of claim 1 or its pharmaceutically
acceptable salts, hydrates, solvates, crystal forms salts and
individual diastereomers thereof.
3. A pharmaceutical composition comprising at least one compound of
claim 1 or its pharmaceutically acceptable salts, hydrates,
solvates, crystal forms salts and individual diastereomers thereof,
and a pharmaceutically acceptable carrier.
4. A compound selected from the group consisting of: ##STR00234##
##STR00235## ##STR00236## ##STR00237## ##STR00238## ##STR00239##
##STR00240## ##STR00241## ##STR00242## ##STR00243## ##STR00244##
##STR00245## ##STR00246## ##STR00247## ##STR00248## ##STR00249##
##STR00250## ##STR00251## ##STR00252## ##STR00253## ##STR00254##
##STR00255## ##STR00256## ##STR00257## ##STR00258## ##STR00259##
##STR00260## ##STR00261## ##STR00262## ##STR00263## ##STR00264##
##STR00265## ##STR00266## ##STR00267## ##STR00268## ##STR00269##
##STR00270## ##STR00271## ##STR00272## ##STR00273## ##STR00274##
##STR00275## ##STR00276## ##STR00277## ##STR00278## ##STR00279##
##STR00280## ##STR00281## ##STR00282## ##STR00283##
##STR00284##
5. The composition according to claim 3, further comprising an
additional therapeutic agent
6. A method for treating a disease or condition in a mammal
characterized by undesired cellular proliferation or
hyperproliferation comprising identifying the mammal afflicted with
said disease or condition and administering to said afflicted
mammal a composition comprising the compound of claim 1.
7. The method of claim 6, wherein the disease or condition is
cancer, stroke, congestive heart failure, an ischemia or
reperfusion injury, arthritis or other arthropathy, retinopathy or
vitreoretinal disease, macular degeneration, autoimmune disease,
vascular leakage syndrome, inflammatory disease, edema, transplant
rejection, burn, or acute or adult respiratory distress
syndrome.
8. The method of claim 7, wherein the disease or condition is
cancer.
9. The method of claim 7, wherein the disease or condition is
autoimmune disease.
10. The method of claim 7, wherein the disease or condition is
stroke.
11. The method of claim 7, wherein the disease or condition is
arthritis.
12. The method of claim 7, wherein the disease or condition is
inflammatory disease.
13. The method of claim 7, wherein the disease or condition is
associated with a kinase.
14. The method according to claim 7, wherein said method further
comprises administering an additional therapeutic agent.
15. The method according to claim 7, wherein said additional
therapeutic agent is a chemotherapeutic agent.
16. The method of claim 13, wherein the kinase is a tyrosine
kinase.
17. The method of claim 13, wherein the kinase is a serine kinase
or a threonine kinase.
18. The method of claim 16, wherein the kinase is an aurora family
kinase.
19. The method of claim 8, wherein said cancer is selected from the
group consisting of cancers of the liver and biliary tree,
intestinal cancers, colorectal cancer, ovarian cancer, small cell
and non-small cell lung cancer, breast cancer, sarcomas,
fibrosarcoma, malignant fibrous histiocytoma, embryonal
rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma,
osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part
sarcoma, neoplasms of the central nervous systems, brain cancer,
and lymphomas, including Hodgkin's lymphoma, lymphoplasmacytoid
lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue
lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma,
Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma, and
combinations thereof.
20. A compound of the formula (II) ##STR00285## or a
pharmaceutically acceptable salt thereof, wherein: Y is selected
from C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, --NR.sup.4R.sup.5, and -Q-R.sup.3; Q is
selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl,
each of which is optionally substituted with C.sub.1-C.sub.6 alkyl
or oxo; R.sup.3 is selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkyl-R.sup.6, aryl, and heteroaryl; R.sup.4 and R.sup.5 are each
independently selected from H, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkyl-R.sup.6; R.sup.6 is selected from hydroxy,
--NH.sub.2, mono(C.sub.1-C.sub.6 alkyl)amino, di(C.sub.1-C.sub.6
alkyl)amino, cycloalkyl, and heterocycloalkyl; X is selected from
--K--Ar.sup.1--R.sup.1, C.sub.1-C.sub.6 alkyl, cycloalkyl, and
heterocycloalkyl, each of which is optionally substituted with
C.sub.1-C.sub.6 alkyl, halogen, hydroxy, amino, cyano, --COOH, or
oxo; K is selected from O and S; Ar.sup.1 is selected from aryl and
heteroaryl; R.sup.1 is selected from H, --NHC(O)W, --C(O)NHW, and
--NH.sub.2; W is selected from C.sub.1-C.sub.6 alkyl, aryl,
heteroaryl, and aryl(C.sub.1-C.sub.6)alkyl, each of which is
optionally substituted with C.sub.1-C.sub.6 alkyl, halogen,
hydroxy, amino, cyano, --COOH, or oxo; Z is
--(NH).sub.n--Ar.sup.2--R.sup.2; n=0, 1; Ar.sup.2 is selected from
aryl and heteroaryl, each of which is optionally substituted with
C.sub.1-C.sub.6 alkyl, halogen, hydroxy, amino, cyano, --COON, or
oxo; R.sup.2 is selected from H, C.sub.1-C.sub.6 alkyl, --NH.sub.2,
.dbd.NH, C.sub.1-C.sub.6 alkoxycarbonyl, halo, and cycloalkyl.
21. A compound of the formula (II) ##STR00286## or a
pharmaceutically acceptable salt thereof, wherein: Y is selected
from C.sub.1-C.sub.6 alkyl, phenyl, morpholinyl, piperidinyl,
pyrrolidinyl, --NR.sup.4R.sup.5, and -Q-R.sup.3; Q is piperazinyl;
R.sup.3 is selected from C.sub.1-C.sub.6 alkyl,
hydroxy(C.sub.1-C.sub.6)alkyl, and pyridinyl; R.sup.4 and R.sup.5
are each independently selected from H, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkyl-R.sup.6; R.sup.6 is selected from morpholinyl
and di(C.sub.1-C.sub.6 alkyl)amino; X is selected from
C.sub.1-C.sub.6 alkyl, methylpiperazinyl, and
--K--Ar.sup.1--R.sup.1; K is selected from O and S; Ar.sup.1 is
phenyl; R.sup.1 is selected from --NHC(O)W, --C(O)NHW, and
--NH.sub.2; W is selected from C.sub.1-C.sub.6 alkyl, phenyl, and
halobenzyl; Z is --(NH).sub.n--Ar.sup.2--R.sup.2; n=0, 1; Ar.sup.2
is selected from methylthiazolyl, pyrazolyl, imidazolyl, triazolyl,
benzimidazolyl, thiadiazolyl, thiazolyl, isoxazolyl, isothiazolyl,
pyrimidinyl, and pyridinyl; R.sup.2 is selected from
C.sub.1-C.sub.6 alkyl, --NH.sub.2, .dbd.NH, C.sub.1-C.sub.6
alkoxycarbonyl, and halo.
22. A process for making compound of claim 20 or its
pharmaceutically acceptable salts, hydrates, solvates, crystal
forms salts and individual diastereomers thereof.
23. A pharmaceutical composition comprising at least one compound
of claim 20 or its pharmaceutically acceptable salts, hydrates,
solvates, crystal forms salts and individual diastereomers thereof,
and a pharmaceutically acceptable carrier.
24. A process for making compound of claim 21 or its
pharmaceutically acceptable salts, hydrates, solvates, crystal
forms salts and individual diastereomers thereof.
25. A pharmaceutical composition comprising at least one compound
of claim 21 or its pharmaceutically acceptable salts, hydrates,
solvates, crystal forms salts and individual diastereomers thereof,
and a pharmaceutically acceptable carrier.
Description
FIELD OF THE INVENTION
[0001] The present invention relates generally to the use of
compounds to treat a variety of disorders, diseases and pathologic
conditions and more specifically to the use of triazine compounds
to modulate protein kinases and for treating protein
kinase-mediated diseases.
BACKGROUND OF THE INVENTION
[0002] Protein kinases constitute a large family of structurally
related enzymes that are responsible for the control of a variety
of signal transduction processes within the cell. Protein kinases,
containing a similar 250-300 amino acid catalytic domain, catalyze
the phosphorylation of target protein substrates.
[0003] The kinases may be categorized into families by the
substrates in the phosphorylate (e.g., protein-tyrosine,
protein-serine/threonine, lipids, etc.). Tyrosine phosphorylation
is a central event in the regulation of a variety of biological
processes such as cell proliferation, migration, differentiation
and survival. Several families of receptor and non-receptor
tyrosine kinases control these events by catalyzing the transfer of
phosphate from ATP to a tyrosine residue of specific cell protein
targets. Sequence motifs have been identified that generally
correspond to each of these kinase families [Hanks et al., FASEB
J., (1995), 9, 576-596; Knighton et al., Science, (1991), 253,
407-414; Garcia-Bustos et al., EMBO J., (1994), 13:2352-2361).
Examples of kinases in the protein kinase family include, without
limitation, abl, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-Met, c-src,
c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,
cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1,
FGFR2, FGFR3, FGFR4, FGFR5, Fgr, fit-1, Fps, Frk, Fyn, Hck, IGF-1R,
INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros,
Tie, Tie-2, TRK, Yes, and Zap70.
[0004] Studies indicated that protein kinases play a central role
in the regulation and maintenance of a wide variety of cellular
processes and cellular function. For example, kinase activity acts
as molecular switches regulating cell proliferation, activation,
and/or differentiation. Uncontrolled or excessive kinase activity
has been observed in many disease states including benign and
malignant proliferation disorders as well as diseases resulting
from inappropriate activation of the immune system (autoimmune
disorders), allograft rejection, and graft vs host disease.
[0005] It is reported that many diseases are associated with
abnormal cellular responses triggered by protein kinase-mediated
events. These diseases include autoimmune diseases, inflammatory
diseases, bone diseases, metabolic diseases, neurological and
neurodegenerative diseases, cancer, cardiovascular diseases,
allergies and asthma, Alzheimer's disease and hormone-related
diseases. In addition, endothelial cell specific receptor PTKs,
such as VEGF-2 and Tie-2, mediate the angiogenic process and are
involved in supporting the progression of cancers and other
diseases involving uncontrolled vascularization. Accordingly, there
has been a substantial effort in medicinal chemistry to find
protein kinase inhibitors that are effective as therapeutic
agents.
[0006] One kinase family of particular interest is the aurora
kinases. The Aurora kinase family is a collection of highly related
serine/threonine kinase that are key regulators of mitosis,
essential for accurate and equal segtion of genomic material from
parent to daught cells. Members of the Aurora kinase family include
three related kinases kown as Aurora-A, Aurora-B, and Aurora-C.
Despite significant sequence homology, the localization and
functions of these kinases are largely distinct from one another
(Richard D. Carvajal, et al. Clin Cancer Res 2006; 12(23):
6869-6875; Daruka Mahadevan, et al. Expert Opin. Drug Discov. 2007
2(7): 1011-1026).
[0007] Aurora-A is ubiquitously expressed and regulates cell cycle
events occurring from late S phase through M phase, including
centrosome maturation (Berdnik D, et al. Curr Biol 2002; 12:640-7),
mitotic entry (Hirota T, et al. Cell 2003; 114:585-98; Dutertre S,
et al. J Cell Sci 2004; 117:2523-31), centrosome separation
(Marumoto T, et al. J Biol Chem 2003; 278:51786-95),
bipolar-spindle assembly (Kufer T A, et al. J Cell Biol 2002;
158:617-23; Eyers P A, et al. Curr Biol 2003; 13:691-7.),
chromosome alignment on the metaphase plate (Marumoto T, et al. J
Biol Chem 2003; 278:51786-95; Kunitoku N, et al. Dev Cell 2003;
5:853-64.), cytokinesis (Marumoto T, et al. J Biol Chem 2003;
278:51786-95), and mitotic exit. Aurora-A protein levels and kinase
activity both increase from late G2 through M phase, with peak
activity in prometaphase. Once activated, Aurora-A mediates its
multiple functions by interacting with various substrates including
centrosomin, transforming acidic coiled-coil protein, cdc25b, Eg5,
and centromere protein A.
[0008] Aurora-B is a chromosomal passenger protein critical for
accurate chromosomal segregation, cytokinesis (Hauf S, et al. J
Cell Biol 2003; 161:281-94; Ditchfield C, et al. J Cell Biol 2003;
161:267-80; Giet R, et al. J Cell Biol 2001; 152:669-82; Goto H, et
al. J Biol Chem 2003; 278:8526-30), protein localization to the
centromere and kinetochore, correct microtubule-kinetochore
attachments (Murata-Hori M, et al. Curr Biol 2002; 12:894-9), and
regulation of the mitotic checkpoint. Aurora-B localizes first to
the chromosomes during prophase and then to the inner centromere
region between sister chromatids during prometaphase and metaphase
(Zeitlin S G, et al. J Cell Biol 2001; 155:1147-57). Aurora-B
participates in the establishment of chromosomal biorientation, a
condition where sister kinetochores are linked to opposite poles of
the bipolar spindle via amphitelic attachments. Errors in this
process, manifesting as a merotelic attachment state (one
kinetochore attached to microtubules from both poles) or a syntelic
attachment state (both sister kinetochores attached to microtubules
from the same pole), lead to chromosomal instability and aneuploidy
if not corrected before the onset of anaphase. The primary role of
Aurora-B at this point of mitosis is to repair incorrect
microtubule-kinetochore attachments (Hauf S, et al. J Cell Biol
2003; 161:281-94; Ditchfield C, et al. J Cell Biol 2003;
161:267-80; Lan W, et al. Curr Biol 2004; 14:273-86.). Without
Aurora-B activity, the mitotic checkpoint is compromised, resulting
in increased numbers of aneuploid cells, genetic instability, and
tumorigenesis (Weaver B A, et al. Cancer Cell 2005; 8:7-12).
[0009] Aurora-A overexpression is a necessary feature of
Aurora-A-induced tumorigenesis. In cells with Aurora-A
overexpression, mitosis is characterized by the presence of
multiple centrosomes and multipolar spindles (Meraldi P et al. EMBO
J 2002; 21:483-92.). Despite the resulting aberrant
microtubule-kinetochore attachments, cells abrogate the mitotic
checkpoint and progress from metaphase to anaphase, resulting in
numerous chromosomal separation defects. These cells fail to
undergo cytokinesis, and, with additional cell cycles, polyploidy
and progressive chromosomal instability develop (Anand S, et al.
Cancer Cell 2003; 3:51-62).
[0010] The evidence linking Aurora overexpression and malignancy
has stimulated interest in developing Aurora inhibitors for cancer
therapy. In normal cells, Aurora-A inhibition results in delayed,
but not blocked, mitotic entry, centrosome separation defects
resulting in unipolar mitotic spindles, and failure of cytokinesis
(Marumoto T, et al. J Biol Chem 2003; 278:51786-95). Encouraging
antitumor effects with Aurora-A inhibition were shown in three
human pancreatic cancer cell lines (Panc-1, MIA PaCa-2, and
SU.86.86), with growth suppression in cell culture and near-total
abrogation of tumorigenicity in mouse xenografts (Hata T, et al.
Cancer Res 2005; 65:2899-905.).
[0011] Aurora-B inhibition results in abnormal
kinetochore-microtubule attachments, failure to achieve chromosomal
biorientation, and failure of cytokinesis (Goto H, et al. J Biol
Chem 2003; 278:8526-30; Severson A F, et al. Curr Biol 2000;
10:1162-71). Recurrent cycles of aberrant itosis without
cytokinesis result in massive polyploidy and, ultimately, to
apoptosis (Hauf S, et al. J Cell Biol 2003; 161:281-94; Ditchfield
C, et al. J Cell Biol 2003; 161:267-80; Giet R, et al. J Cell Biol
2001; 152:669-82; Murata-Hori M, Curr Biol 2002; 12:894-9; Kallio M
J, et al. Curr Biol 2002; 12:900-5).
[0012] Inhibition of Aurora-A or Aurora-B activity in tumor cells
results in impaired chromosome alignment, abrogation of the mitotic
checkpoint, polyploidy, and subsequent cell death. These in vitro
effects are greater in transformed cells than in either
non-transformed or non-dividing cells (Ditchfield C, et al. J Cell
Biol 2003; 161:267-80). Thus, targeting Aurora may achieve in vivo
selectivity for cancer. Although toxicity to rapidly dividing cell
of the hematopoietic and gastrointestinal system is expected, the
activity and clinical tolerability shown in xenograft models
indicates the presence of a reasonable therapeutic index.
[0013] Given the preclinical antitumor activity and potential for
tumor selectivity, several Aurora kinase inhibitors have been
developed. The first three small-molecule inhibitors of Aurora
described include ZM447439 (Ditchfield C, et al. J Cell Biol 2003;
161:267-80), Hesperadin (Hauf S, et al. J Cell Biol 2003;
161:281-94), and MK0457 (VX680) (Harrington E A, et al. Nat Med
2004; 10:262-7). The following agents are nonspecific inhibitors:
ZM447439 inhibits Aurora-A and Aurora-B; Herperadin inhibits
primarily Aurora-B; MK0457 inhibits all three Aurora kinases. Each
induces a similar phenotype in cell-based assays, characterized by
inhibition of phosphorylation of histone H3 on Ser10, inhibition of
cytokinesis, and the development of polyploidy. Selective
inhibitors of Aurora have also been developed. A selective Aurora-A
inhibitor is MLN8054 (Hoar H M, et al. [abstract C40]. Proc
AACR-NCI-EORTC International Conference: Molecular Targets and
Cancer Therapeutics 2005). A expmple of selective Aurora-B
inhibitor is AZD1152 (Schellens J, et al. [abstract 3008]. Proc Am
Soc Clin Oncol 2006; 24:122s). The next generation of Aurora
inhibitors is currently being developed, including agents by
Nerviano Medical Sciences (PHA-680632 and PHA-739358), Rigel
(R763), Sunesis (SNS-314), NCE Discovery Ltd. (NCED#17), Astex
Therapeutics (AT9283), and Montigen Pharmaceuticals (MP-235 and
MP-529). Several of these agents are undergoing evaluation in
clinical trials.
[0014] Considering the lack of currently available treatment
options for the majority of the conditions associated with protein
kinases, there is still a great need for new therapeutic agents for
these conditions.
BRIEF SUMMARY OF THE INVENTION
[0015] Accordingly, one aspect of the present invention provides an
antitumor agent comprising a triazine derivative as described in
formula (I) or formula (II), pharmaceutically-acceptable
formulations thereof, methods for making novel compounds and
compositions for using the compounds. The compounds and
compositions comprising the compounds of formula (I) or formula
(II) have utility in treatment of a variety of diseases.
[0016] The combination therapy described herein may be provided by
the preparation of the triazine derivative of formula (I) or
formula (II) and the other therapeutic agent as separate
pharmaceutical formulations followed by the administration thereof
to a patient simultaneously, semi-simultaneously, separately or
over regular intervals.
[0017] The present invention provides methods of use for certain
chemical compounds such as kinase inhibitors for treatment of
various diseases, disorders, and pathologies, for example, cancer,
and vascular disorders, such as myocardial infarction (MI), stroke,
or ischemia. The triazine compounds described in this invention may
block the enzymatic activity of some or many of the members of the
Aurora kinase family, in addition to blocking the activity of other
receptor and non-receptor kinase. Such compounds may be beneficial
for treatment of the diseases where disorders affect cell motility,
adhesion, and cell cycle progression, and in addition, diseases
with related hypoxic conditions, osteoporosis and conditions, which
result from or are related to increases in vascular permeability,
inflammation or respiratory distress, tumor growth, invasion,
angiogenesis, metastases and apoptosis.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The present invention comprises compounds as shown in
formula (I)
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein:
[0019] W and Y are independently selected from S, O, NR.sub.4,
CR.sub.4 or CR.sub.1;
[0020] R.sub.4 is independently selected from hydrogen or an
optionally substituted C.sub.1-4 aliphatic group.
[0021] R.sub.1 represents hydrogen, halogen, hydroxy, amino, cyano,
alkyl, cycloalkyl, alkenyl, alkynyl, alkylthio, aryl, arylalkyl,
heterocyclic, heteroaryl, heterocycloalkyl, alkylsulfonyl,
alkoxycarbonyl and alkylcarbonyl.
[0022] R.sub.2 is selected from: [0023] (i) amino, alkyl amino,
aryl amino, heteroaryl amino; [0024] (ii) C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl; [0025] (iii)
aryl, heterocyclic, heteroaryl; and [0026] (iv) groups of the
formula (Ia):
##STR00003##
[0027] wherein:
[0028] R.sub.5 represents hydrogen, C.sub.1-C.sub.4 alkyl, oxo;
[0029] X is CH, when R.sub.6 is hydrogen; or X--R.sub.6 is O; or X
is N, R.sub.6 represents groups of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10
aryl or heteroaryl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.2-C.sub.6 alkanoyloxy, mono- and di-(C.sub.3-C.sub.8
cycloalkyl)aminoC.sub.0-C.sub.4alkyl, (4- to 7-membered
heterocycle)C.sub.0-C.sub.4alkyl, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6 alkyl)sulfonamido, and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl, each of which is
substituted with from 0 to 4 substituents independently chosen from
halogen, hydroxy, cyano, amino, --COOH and oxo;
[0030] R.sub.3 is selected from:
[0031] (i) C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl;
[0032] (ii) heterocyclic,
[0033] (iii) K--Ar.
[0034] Ar represents heteroaryl or aryl, each of which is
substituted with from 0 to 4 substituents independently chosen
from: [0035] (1) halogen, hydroxy, amino, amide, cyano, --COOH,
--SO.sub.2NH.sub.2, oxo, nitro and alkoxycarbonyl; and [0036] (2)
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.10
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, mono- and
di-(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6alkyl)sulfonamido and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl; phenylC.sub.0-C.sub.4alkyl
and (4- to 7-membered heterocycle)-C.sub.0-C.sub.4alkyl, each of
which is substituted with from 0 to 4 secondary substituents
independently chosen from halogen, hydroxy, cyano, oxo, imino,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and
C.sub.1-C.sub.4haloalkyl.
[0037] K is selected from
[0038] i) absence;
[0039] ii) O, S, SO, SO.sub.2;
[0040] iii) (CH.sub.2).sub.m, m=0-3, --O(CH.sub.2).sub.p, p=1-3,
--S(CH.sub.2).sub.p, p=1-3, --N(CH.sub.2).sub.p, p=1-3,
--(CH.sub.2).sub.pO, p=1-3;
[0041] iv) NR.sub.7
[0042] R.sub.7 represents hydrogen, alkyl, cycloalkyl, alkenyl,
alkynyl, alkylthio, aryl, arylalkyl.
[0043] The present invention also comprises compounds as shown in
formula (II)
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein:
[0044] Y is selected from C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, --NR.sup.4R.sup.5, and
-Q-R.sup.3;
[0045] Q is selected from aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl, each of which is optionally substituted with
C.sub.1-C.sub.6 alkyl or oxo;
[0046] R.sup.3 is selected from H, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkyl-R.sup.6, aryl, and heteroaryl;
[0047] R.sup.4 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkyl-R.sup.6;
[0048] R.sup.6 is selected from hydroxy, --NH.sub.2,
mono(C.sub.1-C.sub.6 alkyl)amino, di(C.sub.1-C.sub.6 alkyl)amino,
cycloalkyl, and heterocycloalkyl;
[0049] X is selected from --K--Ar.sup.1--R.sup.1, C.sub.1-C.sub.6
alkyl, cycloalkyl, and heterocycloalkyl, each of which is
optionally substituted with C.sub.1-C.sub.6 alkyl, halogen,
hydroxy, amino, cyano, --COOH, or oxo;
[0050] K is selected from O and S;
[0051] Ar.sup.1 is selected from aryl and heteroaryl;
[0052] R.sup.1 is selected from H, --NHC(O)W, --C(O)NHW, and
--NH.sub.2;
[0053] W is selected from C.sub.1-C.sub.6 alkyl, aryl, heteroaryl,
and aryl(C.sub.1-C.sub.6)alkyl, each of which is optionally
substituted with C.sub.1-C.sub.6 alkyl, halogen, hydroxy, amino,
cyano, --COOH, or oxo;
[0054] Z is --(NH).sub.n--Ar.sup.2--R.sup.2;
[0055] n=0, 1;
[0056] Ar.sup.2 is selected from aryl and heteroaryl, each of which
is optionally substituted with C.sub.1-C.sub.6 alkyl, halogen,
hydroxy, amino, cyano, --COOH, or oxo;
[0057] R.sup.2 is selected from H, C.sub.1-C.sub.6 alkyl,
--NH.sub.2, .dbd.NH, C.sub.1-C.sub.6 alkoxycarbonyl, halo, and
cycloalkyl.
[0058] The invention further comprises compounds as shown in
formula (II)
##STR00005##
or a pharmaceutically acceptable salt thereof, wherein:
[0059] Y is selected from C.sub.1-C.sub.6 alkyl, phenyl,
morpholinyl, piperidinyl, pyrrolidinyl, --NR.sup.4R.sup.5, and
-Q-R.sup.3;
[0060] Q is piperazinyl;
[0061] R.sup.3 is selected from C.sub.1-C.sub.6 alkyl,
hydroxy(C.sub.1-C.sub.6)alkyl, and pyridinyl;
[0062] R.sup.4 and R.sup.5 are each independently selected from H,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 alkyl-R.sup.6;
[0063] R.sup.6 is selected from morpholinyl and di(C.sub.1-C.sub.6
alkyl)amino;
[0064] X is selected from C.sub.1-C.sub.6 alkyl, methylpiperazinyl,
and --K--Ar.sup.1--R.sup.1;
[0065] K is selected from O and S;
[0066] Ar.sup.1 is phenyl;
[0067] R.sup.1 is selected from --NHC(O)W, --C(O)NHW, and
--NH.sub.2;
[0068] W is selected from C.sub.1-C.sub.6 alkyl, phenyl, and
halobenzyl;
[0069] Z is --(NH).sub.n--Ar.sup.2--R.sup.2;
[0070] n=0, 1;
[0071] Ar.sup.2 is selected from methylthiazolyl, pyrazolyl,
imidazolyl, triazolyl, benzimidazolyl, thiadiazolyl, thiazolyl,
isoxazolyl, isothiazolyl, pyrimidinyl, and pyridinyl;
[0072] R.sup.2 is selected from C.sub.1-C.sub.6 alkyl, --NH.sub.2,
.dbd.NH, C.sub.1-C.sub.6 alkoxycarbonyl, and halo.
[0073] The following definitions refer to the various terms used
above and throughout the disclosure.
[0074] Compounds are generally described herein using standard
nomenclature. For compounds having asymmetric centers, it should be
understood that (unless otherwise specified) all of the optical
isomers and mixtures thereof are encompassed. In addition,
compounds with carbon-carbon double bonds may occur in Z- and
E-forms, with all isomeric forms of the compounds being included in
the present invention unless otherwise specified. Where a compound
exists in various tautomeric forms, a recited compound is not
limited to any one specific tautomer, but rather is intended to
encompass all tautomeric forms. Certain compounds are described
herein using a general formula that include, variables (e.g. X,
Ar.). Unless otherwise specified, each variable within such a
formula is defined independently of any other variable, and any
variable that occurs more than one time in a formula is defined
independently at each occurrence.
[0075] The term "halo" or "halogen" refers to fluorine, chlorine,
bromine or iodine.
[0076] The term "alkyl" herein alone or as part of another group
refers to a monovalent alkane (hydrocarbon) derived radical
containing from 1 to 12 carbon atoms unless otherwise defined.
Alkyl groups may be substituted at any available point of
attachment. An alkyl group substituted with another alkyl group is
also referred to as a "branched alkyl group". Exemplary alkyl
groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl,
isobutyl, pentyl, hexyl, isohexyl, heptyl, dimethylpentyl, octyl,
2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the
like. Exemplary substituents include but are not limited to one or
more of the following groups: alkyl, aryl, halo (such as F, Cl, Br,
I), haloalkyl (such as CCl.sub.3 or CF.sub.3), alkoxy, alkylthio,
hydroxy, carboxy (--COOH), alkyloxycarbonyl (--C(O)R),
alkylcarbonyloxy (--OCOR), amino (--NH.sub.2), carbamoyl
(--NHCOOR-- or --OCONHR--), urea (--NHCONHR--) or thiol (--SH). In
some preferred embodiments of the present invention, alkyl groups
are substituted with, for example, amino, heterocycloalkyl, such as
morpholine, piperazine, piperidine, azetidine, hydroxyl, methoxy,
or heteroaryl groups such as pyrrolidine. "Alkyl" also includes
cycloalkyl.
[0077] The term "cycloalkyl" herein alone or as part of another
group refers to fully saturated and partially unsaturated
hydrocarbon rings of 3 to 9, preferably 3 to 7 carbon atoms. The
examples include cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl, and like. Further, a cycloalkyl may be substituted. A
substituted cycloalkyl refers to such rings having one, two, or
three substituents, selected from the group consisting of halo,
alkyl, substituted alkyl, alkenyl, alkynyl, nitro, cyano, oxo
(.dbd.O), hydroxy, alkoxy, thioalkyl, --CO.sub.2H, --C(.dbd.O)H,
CO.sub.2-alkyl, --C(.dbd.O)alkyl, keto, .dbd.N--OH,
.dbd.N--O-alkyl, aryl, heteroaryl, heterocyclo, --NR'R'',
--C(.dbd.O)NR'R'', --CO.sub.2NR'R'', --C(.dbd.O)NR'R'',
--NR'CO.sub.2R'', --NR'C(.dbd.O)R'', --SO.sub.2NR'R'', and
--NR'SO.sub.2R'', wherein each of R' and R'' are independently
selected from hydrogen, alkyl, substituted alkyl, and cycloalkyl,
or R' and R'' together form a heterocyclo or heteroaryl ring.
[0078] The term "alkenyl" herein alone or as part of another group
refers to a hydrocarbon radical straight, branched or cyclic
containing from 2 to 12 carbon atoms and at least one carbon to
carbon double bond. Examples of such groups include the vinyl,
allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl,
2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
1-heptenyl, and like. Alkenyl groups may also be substituted at any
available point of attachment. Exemplary substituents for alkenyl
groups include those listed above for alkyl groups, and especially
include C.sub.3 to C.sub.7 cycloalkyl groups such as cyclopropyl,
cyclopentyl and cyclohexyl, which may be further substituted with,
for example, amino, oxo, hydroxyl, etc.
[0079] The term "alkynyl" refers to straight or branched chain
alkyne groups, which have one or more unsaturated carbon-carbon
bonds, at least one of which is a triple bond. Alkynyl groups
include C.sub.2-C.sub.8 alkynyl, C.sub.2-C.sub.6 alkynyl and
C.sub.2-C.sub.4 alkynyl groups, which have from 2 to 8, 2 to 6 or 2
to 4 carbon atoms, respectively. Illustrative of the alkynyl group
include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl,
pentenyl, and hexenyl. Alkynyl groups may also be substituted at
any available point of attachment. Exemplary substituents for
alkynyl groups include those listed above for alkyl groups such as
amino, alkylamino, etc. The numbers in the subscript after the
symbol "C" define the number of carbon atoms a particular group can
contain.
[0080] The term "alkoxy" alone or as part of another group denotes
an alkyl group as described above bonded through an oxygen linkage
(--O--). Preferred alkoxy groups have from 1 to 8 carbon atoms.
Examples of such groups include the methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy,
n-pentyloxy, isopentyloxy, n-hexyloxy, cyclohexyloxy, n-heptyloxy,
n-octyloxy and 2-ethylhexyloxy.
[0081] The term "alkylthio" refers to an alkyl group as described
above attached via a sulfur bridge. Preferred alkoxy and alkylthio
groups are those in which an alkyl group is attached via the
heteroatom bridge. Preferred alkylthio groups have from 1 to 8
carbon atoms. Examples of such groups include the methylthio,
ethylthio, n-propythiol, n-butylthiol, and like.
[0082] The term "oxo," as used herein, refers to a keto (C.dbd.O)
group. An oxo group that is a substituent of a nonaromatic carbon
atom results in a conversion of --CH.sub.2-- to --C(.dbd.O)--.
[0083] The term "alkoxycarbonyl" herein alone or as part of another
group denotes an alkoxy group bonded through a carbonyl group. An
alkoxycarbonyl radical is represented by the formula: --C(O)OR,
where the R group is a straight or branched C.sub.1-C.sub.6 alkyl
group, cycloalkyl, aryl, or heteroaryl.
[0084] The term "alkylcarbonyl" herein alone or as part of another
group refers to an alkyl group bonded through a carbonyl group or
--C(O)R.
[0085] The term "arylalkyl" herein alone or as part of another
group denotes an aromatic ring bonded through an alkyl group (such
as benzyl) as described above.
[0086] The term "aryl" herein alone or as part of another group
refers to monocyclic or bicyclic aromatic rings, e.g. phenyl,
substituted phenyl and the like, as well as groups which are fused,
e.g., napthyl, phenanthrenyl and the like. An aryl group thus
contains at least one ring having at least 6 atoms, with up to five
such rings being present, containing up to 20 atoms therein, with
alternating (resonating) double bonds between adjacent carbon atoms
or suitable heteroatoms. Aryl groups may optionally be substituted
with one or more groups including, but not limited to halogen such
as I, Br, F, or Cl; alkyl, such as methyl, ethyl, propyl, alkoxy,
such as methoxy or ethoxy, hydroxy, carboxy, carbamoyl,
alkyloxycarbonyl, nitro, alkenyloxy, trifluoromethyl, amino,
cycloalkyl, aryl, heteroaryl, cyano, alkyl S(O).sub.n, (m=0, 1, 2),
or thiol.
[0087] The term "aromatic" refers to a cyclically conjugated
molecular entity with a stability, due to delocalization,
significantly greater than that of a hypothetical localized
structure, such as the Kekule structure.
[0088] The term "amino" herein alone or as part of another group
refers to --NH.sub.2. An "amino" may optionally be substituted with
one or two substituents, which may be the same or different, such
as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl,
heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl,
cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
thioalkyl, carbonyl or carboxyl. These substituents may be further
substituted with a carboxylic acid, any of the alkyl or aryl
substituents set out herein. In some embodiments, the amino groups
are substituted with carboxyl or carbonyl to form N-acyl or
N-carbamoyl derivatives.
[0089] The term "alkylsulfonyl" refers to groups of the formula
(SO.sub.2)-alkyl, in which the sulfur atom is the point of
attachment. Preferably, alkylsulfonyl groups include
C.sub.1-C.sub.6 alkylsulfonyl groups, which have from 1 to 6 carbon
atoms. Methylsulfonyl is one representative alkylsulfonyl
group.
[0090] The term "heteroatom" refers to any atom other than carbon,
for example, N, O, or S.
[0091] The term "heteroaryl" herein alone or as part of another
group refers to substituted and unsubstituted aromatic 5 or 6
membered monocyclic groups, 9 or 10 membered bicyclic groups, and
11 to 14 membered tricyclic groups which have at least one
heteroatom (O, S or N) in at least one of the rings. Each ring of
the heteroaryl group containing a heteroatom can contain one or two
oxygen or sulfur atoms and/or from one to four nitrogen atoms
provided that the total number of heteroatoms in each ring is four
or less and each ring has at least one carbon atom.
[0092] The fused rings completing the bicyclic and tricyclic groups
may contain only carbon atoms and may be saturated, partially
saturated, or unsaturated. The nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen atoms may optionally be
quaternized. Heteroaryl groups which are bicyclic or tricyclic must
include at least one fully aromatic ring but the other fused ring
or rings may be aromatic or non-aromatic. The heteroaryl group may
be attached at any available nitrogen or carbon atom of any ring.
The heteroaryl ring system may contain zero, one, two or three
substituents selected from the group consisting of halo, alkyl,
substituted alkyl, alkenyl, alkynyl, aryl, nitro, cyano, hydroxy,
alkoxy, thioalkyl, --CO.sub.2H, --C(.dbd.O)H, --CO.sub.2-alkyl,
--C(.dbd.O)alkyl, phenyl, benzyl, phenylethyl, phenyloxy,
phenylthio, cycloalkyl, substituted cycloalkyl, heterocyclo,
heteroaryl, --NR'R'', --C(.dbd.O)NR'R'', --CO.sub.2NR'R'',
--C(.dbd.O)NR'R'', --NR'CO.sub.2R'', --NR'C(.dbd.O)R'',
--SO.sub.2NR'R'', and --NR'SO.sub.2R'', wherein each of R' and R''
is independently selected from hydrogen, alkyl, substituted alkyl,
and cycloalkyl, or R' and R'' together form a heterocyclo or
heteroaryl ring.
[0093] Preferably monocyclic heteroaryl groups include pyrrolyl,
pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, diazolyl, isoxazolyl,
thiazolyl, thiadiazolyl, S isothiazolyl, furanyl, thienyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
triazinyl and the like.
[0094] Preferably bicyclic heteroaryl groups include indolyl,
benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl,
quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl,
benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl,
benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
dihydroisoindolyl, tetrahydroquinolinyl and the like.
[0095] Preferably tricyclic heteroaryl groups include carbazolyl,
benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl
and the like.
[0096] The term "heterocycle" or "heterocycloalkyl" herein alone or
as part of another group refers to a cycloalkyl group (nonaromatic)
in which one of the carbon atoms in the ring is replaced by a
heteroatom selected from O, S or N. The "heterocycle" has from 1 to
3 fused, pendant or spiro rings, at least one of which is a
heterocyclic ring (i.e., one or more ring atoms is a heteroatom,
with the remaining ring atoms being carbon). The heterocyclic ring
may be optionally substituted which means that the heterocyclic
ring may be substituted at one or more substitutable ring positions
by one or more groups independently selected from alkyl (preferably
lower alkyl), heterocycloalkyl, heteroaryl, alkoxy (preferably
lower alkoxy), nitro, monoalkylamino (preferably a lower
alkylamino), dialkylamino (preferably a alkylamino), cyano, halo,
haloalkyl (preferably trifluoromethyl), alkanoyl, aminocarbonyl,
monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl amido
(preferably lower alkyl amido), alkoxyalkyl (preferably a lower
alkoxy; lower alkyl), alkoxycarbonyl (preferably a lower
alkoxycarbonyl), alkylcarbonyloxy (preferably a lower
alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being
optionally substituted by halo, lower alkyl and lower alkoxy
groups. A heterocyclic group may generally be linked via any ring
or substituent atom, provided that a stable compound results.
N-linked heterocyclic groups are linked via a component nitrogen
atom.
[0097] Typically, a heterocyclic ring comprises 1-4 heteroatoms;
within certain embodiments each heterocyclic ring has 1 or 2
heteroatoms per ring. Each heterocyclic ring generally contains
from 3 to 8 ring members (rings having from to 7 ring members are
recited in certain embodiments), and heterocycles comprising fused,
pendant or spiro rings typically contain from 9 to 14 ring members
which consists of carbon atoms and contains one, two, or three
heteroatoms selected from nitrogen, oxygen and/or sulfur.
[0098] Examples of "heterocycle" or "heterocycloalkyl groups
include piperazine, piperidine, morpholine, thiomorpholine,
pyrrolidine, imidazolidine and thiazolide.
[0099] The term "substituent," as used herein, refers to a
molecular moiety that is covalently bonded to an atom within a
molecule of interest. For example, a "ring substituent" may be a
moiety such as a halogen, alkyl group, haloalkyl group or other
group discussed herein that is covalently bonded to an atom
(preferably a carbon or nitrogen atom) that is a ring member.
[0100] The term "optionally substituted" as it refers that the aryl
or heterocyclyl or other group may be substituted at one or more
substitutable positions by one or more groups independently
selected from alkyl (preferably lower alkyl), alkoxy (preferably
lower alkoxy), nitro, monoalkylamino (preferably with one to six
carbons), dialkylamino (preferably with one to six carbons), cyano,
halo, haloalkyl (preferably trifluoromethyl), alkanoyl,
aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkyl
amido (preferably lower alkyl amido), alkoxyalkyl (preferably a
lower alkoxy and lower alkyl), alkoxycarbonyl (preferably a lower
alkoxycarbonyl), alkylcarbonyloxy (preferably a lower
alkylcarbonyloxy) and aryl (preferably phenyl), said aryl being
optionally substituted by halo, lower alkyl and lower alkoxy
groups. Optional substitution is also indicated by the phrase
"substituted with from 0 to X substituents," where X is the maximum
number of possible substituents. Certain optionally substituted
groups are substituted with from 0 to 2, 3 or 4 independently
selected substituents.
[0101] A dash ("-") that is not between two letters or symbols is
used to indicate a point of t attachment for a substituent. For
example, --CONH.sub.2 is attached through the carbon atom.
[0102] A dashed cycle that locates inside of a heterocyle ring is
used to indicate a conjugated system. The bonds between two atomes
may be single bond or double bond.
[0103] The term "anticancer" agent includes any known agent that is
useful for the treatment of cancer including, but is not limited,
Acivicin; Aclarubicin; Acodazole Hydrochloride; AcrQnine;
Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone
Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin;
Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin;
Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride;
Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar
Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone;
Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin
Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin;
Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide;
Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride;
Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate;
Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride;
Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;
Duazomycin; Edatrexate; Eflomithine Hydrochloride; Elsamitrucin;
Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride;
Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine
Phosphate Sodium; Etanidazole; Ethiodized Oil I 131; Etoposide;
Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine;
Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil;
Fluorocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin
Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;
Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3;
Interferon Beta-I a; Interferon Gamma-I b; Iproplatin; Irinotecan
Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate;
Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone
Hydrochloride; Masoprocol; Maytansine; Mechlorethamine
Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan;
Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium;
Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin;
Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone
Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;
Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;
Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman;
Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine
Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin;
Riboprine; Rogletimide; Safmgol; Safingol Hydrochloride; Semustine;
Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium
Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin;
Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin;
Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone
Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;
Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine;
Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate;
Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate;
Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa;
Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate;
Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate
Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine
Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and
Zorubicin Hydrochloride.
[0104] The term "kinase" refers to any enzyme that catalyzes the
addition of phosphate groups to a protein residue; for example,
serine and threonine kineses catalyze the addition of phosphate
groups to serine and threonine residues.
[0105] The terms "Src kinase," "Src kinase family," and "Src
family" refer to the related homologs or analogs belonging to the
mammalian family of Src kineses, including, for example, c-Src,
Fyn, Yes and Lyn kineses and the hematopoietic-restricted kineses
Hck, Fgr, Lck and Blk.
[0106] The term "therapeutically effective amount" refers to the
amount of the compound or pharmaceutical composition that will
elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher,
veterinarian, medical doctor or other clinician, e.g., restoration
or maintenance of vasculostasis or prevention of the compromise or
loss or vasculostasis; reduction of tumor burden; reduction of
morbidity and/or mortality.
[0107] The term "pharmaceutically acceptable" refers to the fact
that the carrier, diluent or excipient must be compatible with the
other ingredients of the formulation and not deleterious to the
recipient thereof.
[0108] The terms "administration of a compound" or "administering a
compound" refer to the act of providing a compound of the invention
or pharmaceutical composition to the subject in need of
treatment.
[0109] The term "protected" refers that the group is in modified
form to preclude undesired side reactions at the protected site.
Suitable protecting groups for the compounds of the present
invention will be recognized from the present application taking
into account the level of skill in the art, and with reference to
standard textbooks, such as Greene, T. W. et al., Protective Groups
in Organic Synthesis, John Wiley & Sons, New York (1999).
[0110] The term "pharmaceutically acceptable salt" of a compound
recited herein is an acid or base salt that is suitable for use in
contact with the tissues of human beings or animals without
excessive toxicity or carcinogenicity, and preferably without
irritation, allergic response, or other problem or complication.
Such salts include mineral and organic acid salts of basic residues
such as amines, as well as alkali or organic salts of acidic
residues such as carboxylic acids. Specific pharmaceutical salts
include, but are not limited to, salts of acids such as
hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric,
sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic,
methanesulfonic, benzene sulfonic, ethane disulfonic,
2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric,
tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic,
succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic,
phenylacetic, alkanoic such as acetic, HOOC--
(CH.sub.2).sub.n--COOH where n is 0-4, and the like. Similarly,
pharmaceutically acceptable cations include, but are not limited to
sodium, potassium, calcium, aluminum, lithium and ammonium. Those
of ordinary skill in the art will recognize further
pharmaceutically acceptable salts for the compounds provided
herein. In general, a pharmaceutically acceptable acid or base salt
can be synthesized from a parent compound that contains a basic or
acidic moiety by any conventional chemical method. Briefly, such
salts can be prepared by reacting the free acid or base forms of
these compounds with a stoichiometric amount of the appropriate
base or acid in water or in an organic solvent, or in a mixture of
the two; generally, the use of nonaqueous media, such as ether,
ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.
It will be apparent that each compound of formula (I) or formula
(II) may, but need not, be formulated as a hydrate, solvate or
non-covalent complex. In addition, the various crystal forms and
polymorphs are within the scope of the present invention. Also
provided herein are prodrugs of the compounds of formula (I) or
formula (II).
[0111] The term of "prodrug" refers a compound that may not fully
satisfy the structural requirements of the compounds provided
herein, but is modified in vivo, following administration to a
patient, to produce a compound of formula (I) or formula (II), or
other formula provided herein. For example, a prodrug may be an
acylated derivative of a compound as provided herein. Prodrugs
include compounds wherein hydroxy, amine or thiol groups are bonded
to any group that, when administered to a mammalian subject,
cleaves to form a free hydroxy, amino, or thiol group,
respectively. Examples of prodrugs include, but are not limited to,
acetate, formate and benzoate derivatives of alcohol and amine
functional groups within the compounds provided herein. Prodrugs of
the compounds provided herein may be prepared by modifying
functional groups present in the compounds in such a way that the
modifications are cleaved in vivo to yield the parent
compounds.
[0112] Groups that are "optionally substituted" are unsubstituted
or are substituted by other than hydrogen at one or more available
positions. Such optional substituents include, for example,
hydroxy, halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.2-C.sub.6 alkyl ether, C.sub.3-C.sub.6 alkanone,
C.sub.2-C.sub.6 alkylthio, amino, mono- or di-(C.sub.1-C.sub.6
alkyl)amino, C.sub.1-C.sub.6 haloalkyl, --COOH, --CONH.sub.2, mono-
or di-(C.sub.1-C.sub.6 alkyl)aminocarbonyl, --SO.sub.2NH.sub.2,
and/or mono or di(C.sub.1-C.sub.6 alkyl)sulfonamido, as well as
carbocyclic and heterocyclic groups.
[0113] Optional substitution is also indicated by the phrase
"substituted with from 0 to X substituents," where X is the maximum
number of possible substituents. Certain optionally substituted
groups are substituted with from 0 to 2, 3 or 4 independently
selected substituents.
[0114] Preferred R.sub.1 groups of formula (I) are listed
below:
[0115] Hydrogen, halogen, hydroxy, amino, cyano, alkyl, cycloalkyl,
alkenyl, alkynyl, alkylthio, aryl, arylalkyl, heterocyclic,
heteroaryl, heterocycloalkyl, alkylsulfonyl, alkoxycarbonyl and
alkylcarbonyl.
[0116] Preferred R.sub.2 groups of formula (I) are listed
below:
##STR00006## ##STR00007## ##STR00008## ##STR00009##
##STR00010##
[0117] Preferred R.sub.3 groups of formula (I) are listed below,
wherein the substitute may be the specific ones as defined here or
may be one or multiple substitutes as defined above:
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## ##STR00027## ##STR00028## ##STR00029##
##STR00030##
[0118] R.sub.4 is independently selected from hydrogen or an
optionally substituted C.sub.1-4 aliphatic group.
[0119] Preferably, the compounds of the invention may be compounds
of formula (I) wherein
[0120] R.sub.1 groups of formula (I) are listed below:
[0121] --H, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
iso-propyl, cyclopropyl, cyclobutyl, tert-butyl, --CH.sub.2OH,
--COOCH.sub.2CH.sub.3, --Cl, --F, --Br.
[0122] W and Y are independently selected from S, O, NR.sub.4,
CR.sub.4 or CR.sub.1;
[0123] R.sub.4 is independently selected from hydrogen or an
optionally substituted C.sub.1-4 aliphatic group.
[0124] n is 1 or 2.
[0125] R.sub.2 is selected from: [0126] (i) amino, alkyl amino,
aryl amino, heteroaryl amino; [0127] (ii) C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl; [0128] (iii)
aryl, heterocyclic, heteroaryl; and [0129] (iv) groups of the
formula (Ia):
##STR00031##
[0130] wherein:
[0131] R.sub.5 represents hydrogen, C.sub.1-C.sub.4 alkyl, oxo;
[0132] X is CH, when R.sub.6 is hydrogen; or X--R.sub.6 is O; or X
is N, R.sub.6 represents groups of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10
aryl or heteroaryl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.2-C.sub.6 alkanoyloxy, mono- and di-(C.sub.3-C.sub.8
cycloalkyl)aminoC.sub.0-C.sub.4alkyl, (4- to 7-membered
heterocycle)C.sub.0-C.sub.4alkyl, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6 alkyl)sulfonamido, and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl, each of which is
substituted with from 0 to 4 substituents independently chosen from
halogen, hydroxy, cyano, amino, --COOH and oxo;
[0133] R.sub.3 is selected from:
[0134] (i) C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl;
[0135] (ii) heterocyclic,
[0136] (iii) K--Ar.
[0137] Ar represents heteroaryl or aryl, each of which is
substituted with from 0 to 4 substituents independently chosen
from: [0138] (1) halogen, hydroxy, amino, amide, cyano, --COOH,
--SO.sub.2NH.sub.2, oxo, nitro and alkoxycarbonyl; and [0139] (2)
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.10
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, mono- and
di-(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6alkyl)sulfonamido and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl; phenylC.sub.0-C.sub.4alkyl
and (4- to 7-membered heterocycle)-(C.sub.0-C.sub.4alkyl, each of
which is substituted with from 0 to 4 secondary substituents
independently chosen from halogen, hydroxy, cyano, oxo, imino,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and
C.sub.1-C.sub.4haloalkyl.
[0140] K is selected from
[0141] i) absence;
[0142] ii) O, S, SO, SO.sub.2;
[0143] iii) (CH.sub.2).sub.m, m=0-3, --O(CH.sub.2).sub.p, p=1-3,
--S(CH.sub.2).sub.p, p=1-3, --N(CH.sub.2).sub.p, p=1-3,
--(CH.sub.2).sub.pO, p=1-3;
[0144] iv) NR.sub.7
[0145] R.sub.7 represents hydrogen, alkyl, cycloalkyl, alkenyl,
alkynyl, alkylthio, aryl, arylalkyl.
[0146] More preferably, the compounds of the invention may be
compounds of formula (I) wherein
[0147] R.sub.1 represents --H, --Cl, --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3, cyclopropyl,
cyclobutyl, --CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3).sub.3,
Ph.
[0148] W and Y are independently selected from S, O, NR.sub.4, or
CR.sub.4;
[0149] R.sub.4 is independently selected from hydrogen or an
optionally substituted C.sub.1-4 aliphatic group.
[0150] n is 1;
[0151] R.sub.2 is selected from:
[0152] (i) amino, alkyl amino, aryl amino, heteroaryl amino;
[0153] (ii) C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl;
[0154] (iii) aryl, heterocyclic, heteroaryl; and
[0155] (iv) groups of the formula (Ia):
##STR00032##
[0156] wherein:
[0157] R.sub.5 represents hydrogen, C.sub.1-C.sub.4 alkyl, oxo;
[0158] X is CH, when R.sub.6 is hydrogen; or X--R.sub.6 is O; or X
is N, R.sub.6 represents groups of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10
aryl or heteroaryl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.2-C.sub.6 alkanoyloxy, mono- and di-(C.sub.3-C.sub.8
cycloalkyl)aminoC.sub.0-C.sub.4alkyl, (4- to 7-membered
heterocycle)C.sub.0-C.sub.4alkyl, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6 alkyl)sulfonamido, and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl, each of which is
substituted with from 0 to 4 substituents independently chosen from
halogen, hydroxy, cyano, amino, --COOH and oxo;
[0159] R.sub.3 is selected from:
[0160] (i) C.sub.1-C.sub.0 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl;
[0161] (ii) heterocyclic,
[0162] (iii) K--Ar.
[0163] Ar represents heteroaryl or aryl, each of which is
substituted with from 0 to 4 substituents independently chosen
from: [0164] (1) halogen, hydroxy, amino, amide, cyano, --COOH,
--SO.sub.2NH.sub.2, oxo, nitro and alkoxycarbonyl; and [0165] (2)
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.10
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, mono- and
di-(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6alkyl)sulfonamido and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl; phenylC.sub.0-C.sub.4alkyl
and (4- to 7-membered heterocycle)-C.sub.0-C.sub.4alkyl, each of
which is substituted with from 0 to 4 secondary substituents
independently chosen from halogen, hydroxy, cyano, oxo, imino,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and
C.sub.1-C.sub.4haloalkyl.
[0166] K is selected from
[0167] i) absence;
[0168] ii) O, S,
[0169] (iii) ((CH.sub.2).sub.m, m=0-3, --O(CH.sub.2).sub.p, p=1-3,
--S(CH.sub.2).sub.p, p=1-3, --N(CH.sub.2).sub.p, p=1-3,
--(CH.sub.2).sub.p0, p=1-3;
[0170] iv) NR.sub.7
[0171] R.sub.7 represents hydrogen, alkyl, cycloalkyl, alkenyl,
alkynyl, alkylthio, aryl, arylalkyl.
[0172] Most preferably, the compounds of the invention may be
compounds of formula (I) wherein
[0173] R.sub.1 represents --Cl, --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, cyclopropanyl, cyclobutyl,
--CH.sub.2CH(CH.sub.3).sub.2, --CH(CH.sub.3).sub.3.
[0174] W and Y are independently selected from S, NR.sub.4, or
CR.sub.4;
[0175] R.sub.4 is independently selected from hydrogen or an
optionally substituted C.sub.1-4 aliphatic group.
[0176] n is 1;
[0177] R.sub.2 is selected from:
[0178] (i) amino, alkyl amino, aryl amino, heteroaryl amino;
[0179] (ii) C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl;
[0180] (iii) groups of the formula (Ia):
##STR00033##
[0181] wherein:
[0182] R.sub.5 represents hydrogen, C.sub.1-C.sub.1 alkyl, oxo;
[0183] X is CH, when R.sub.6 is hydrogen; or X--R.sub.6 is O; or X
is N, R.sub.6 represents groups of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10
aryl or heteroaryl,
(C.sub.3-C.sub.7cycloalkyl)C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 alkoxycarbonyl,
C.sub.2-C.sub.6 alkanoyloxy, mono- and di-(C.sub.3-C.sub.8
cycloalkyl)aminoC.sub.0-C.sub.4alkyl, (4- to 7-membered
heterocycle)C.sub.0-C.sub.4alkyl, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6 alkyl)sulfonamido, and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl, each of which is
substituted with from 0 to 4 substituents independently chosen from
halogen, hydroxy, cyano, amino, --COOH and oxo;
[0184] R.sub.3 is selected from:
[0185] K--Ar.
[0186] Ar represents heteroaryl or aryl, each of which is
substituted with from 0 to 4 substituents independently chosen
from: [0187] (1) halogen, hydroxy, amino, amide, cyano, and [0188]
(2) C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.10
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, mono- and
di-(C.sub.1-C.sub.6alkyl)amino, C.sub.1-C.sub.6 alkylsulfonyl,
mono- and di-(C.sub.1-C.sub.6alkyl)sulfonamido and mono- and
di-(C.sub.1-C.sub.6alkyl)aminocarbonyl; phenylC.sub.0-C.sub.4alkyl
and (4- to 7-membered heterocycle)-C.sub.0-C.sub.4alkyl, each of
which is substituted with from 0 to 4 secondary substituents
independently chosen from halogen, hydroxy, cyano, oxo, imino,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy and
C.sub.1-C.sub.4haloalkyl.
[0189] K is selected from
[0190] (i) O, S,
[0191] (ii) --O(CH.sub.2).sub.p, p=1-3, --S(CH.sub.2).sub.p, p=1-3,
--N(CH.sub.2).sub.p, p=1-3;
[0192] (iii) NR.sub.7
[0193] R.sub.7 represents hydrogen, alkyl.
[0194] Preferred heterocyclic groups in compounds of formula (I)
include
##STR00034##
[0195] Which optionally may be substituted.
[0196] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is
hydrogen.
[0197] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is chloro.
[0198] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is methyl.
[0199] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is ethyl.
[0200] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is propyl.
[0201] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is
isopropyl.
[0202] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is
isobutyl.
[0203] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is
tert-butyl.
[0204] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is
cyclopropyl.
[0205] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.1 is
cyclobutyl.
[0206] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.2 is
methyl-piperazinyl.
[0207] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.2 is
(2-hydroxylethyl)-piperazinyl.
[0208] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.2 is
(4-pyridinyl)-piperazinyl.
[0209] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.2 is methyl.
[0210] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.2 is ethyl.
[0211] According to another embodiment, the present invention
relates to a compound of formula (I) wherein R.sub.2 is
cyclopropyl.
[0212] Examples of specific compounds of the present invention are
those compounds defined in the following:
##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054##
##STR00055## ##STR00056## ##STR00057## ##STR00058## ##STR00059##
##STR00060## ##STR00061## ##STR00062## ##STR00063## ##STR00064##
##STR00065## ##STR00066## ##STR00067## ##STR00068## ##STR00069##
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079##
##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084##
##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089##
##STR00090## ##STR00091## ##STR00092## ##STR00093##
[0213] In another embodiment, a method of preparing the inventive
compounds is provided. The compounds of the present invention can
be generally prepared using cyanuric chloride as a starting
material. Compounds of formula (I) or formula (II) may contain
various stereoisomers, geometric isomers, tautomeric isomers, and
the like. All of possible isomers and their mixtures are included
in the present invention, and the mixing ratio is not particularly
limited.
[0214] The triazine derivative compounds of formula (I) or formula
(II) in this invention can be prepared by known procedure in the
prior art. The examples could be found in US Patent Application
Publication No. 2005/0250945A1; US Patent Application Publication
No. 2005/0227983A1; PCT WO 05/007646A1; PCT WO 05/007648A2; PCT WO
05/003103A2; PCT WO 05/011703 A1; and J. Med. Chem. (2004), 47(19),
4649-4652. Starting materials are commercially available from
suppliers such as Sigma-Aldrich Corp. (St. Louis, Mo.), or may be
synthesized from commercially available precursors using
established protocols. By way of example, a synthetic route similar
to that shown in any of the following Schemes may be used, together
with synthetic methods known in the art of synthetic organic
chemistry, or variations thereon as appreciated by those skilled in
the art. Each variable in the following schemes refers to any group
consistent with the description of the compounds provided
herein.
[0215] In the Schemes that follow the term "reduction" refers to
the process of reducing a nitro functionality to an amino
functionality, or the process of transforming an ester
functionality to an alcohol. The reduction of a nitro group can be
carried out in a number of ways well known to those skilled in the
art of organic synthesis including, but not limited to, catalytic
hydrogenation, reduction with SnCl.sub.2 and reduction with
titanium bichloride. The reduction of an ester group is typically
performed using metal hydride reagents including, but not limited
to, diisobutyl-aluminum hydride (DIBAL), lithium aluminum hydride
(LAH), and sodium borohydride. For an overview of reduction methods
see: Hudlicky, M. Reductions in Organic Chemistry, ACS Monograph
188, 1996. In the Schemes that follow, the term "hydrolyze" refers
to the reaction of a substrate or reactant with water. More
specifically, "hydrolyze" refers to the conversion of an ester or
nitrite functionality into a carboxylic acid. This process can be
catalyzed by a variety of acids or bases well known to those
skilled in the art of organic synthesis.
[0216] The compounds of formula (I) or formula (II) may be prepared
by use of known chemical reactions and procedures. The following
general preparative methods are presented to aid one of skill in
the art in synthesizing the inhibitors, with more detailed examples
being presented in the experimental section describing the working
examples.
[0217] Heterocyclic amines are defined in formula (III). Some of
heterocyclic amines are commercially available, others may be
prepared by known procedure in the prior art (Katritzky, et al.
Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK,
1984, March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New
York, 1985), or by using common knowledge of organic chemistry.
##STR00094##
[0218] For example, substituted heterocyclic amines can be
generated using standard methods (March, J. Advanced Organic
Chemistry, 4th Ed.; John Wiley, New York (1992); Larock, R. C.
Comprehensive Organic Transformations, 2nd Ed., John Wiley, New
York (1999); PCT WO 99/32106). As shown in Scheme 1, heterocyclic
amines can be commonly synthesized by reduction of nitroheteros
using a metal catalyst, such as Ni, Pd, or Pt, and H.sub.2 or a
hydride transfer agent, such as formate, cyclohexadiene, or a
borohydride (Rylander. Hydrogenation Methods; Academic Press:
London, UK (1985)). Nitroheteros may also be directly reduced using
a strong hydride source, such as LAH, (Seyden-Penne. Reductions by
the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers:
New York (1991)), or using a zero valent metal, such as Fe, Sn or
Ca, often in acidic media. Many methods exist for the synthesis of
nitroaryls (March, J. Advanced Organic Chemistry, 4th Ed.; John
Wiley, New York (1992); Larock, R. C. Comprehensive Organic
Transformations, 2nd Ed., John Wiley, New York (1999))).
##STR00095##
[0219] As illustrated in Scheme 2, thiazole amine with a
substituent (IIIb) can be prepared from commercial compounds as
illustrated in Scheme 2. By Route 1, a substituted aldehyde, which
may be commercially available or prepared by oxidizing an alcohole,
can be brominated by broming or NBS (N-Bromosuccinimide); after
bromination, the aldehyde can be converted to the corresponding
thiazole amine (IIIb) by reacting with thiourea. For the oxidation
step, a variety of oxidizing reagent can be used, such as
pyridinium chlorochromate (PCC) activated dimethyl sulfoxide
(DMSO), hypervalent iodide compounds, Tetrapropylammonium
perruthenate (TPAP) or 2,2,6,6-Tetramethylpiperidine-1-oxyl
(TEMPO). A lot of thiazole amines can be prepared by this way.
##STR00096##
[0220] A lot of substituted pyrazole amines are commercially
available and can be used directly. In some special case, pyrazole
amines with a substituent (IIIc) can be prepared by known procedure
in the prior art, such as U.S. Pat. No. 6,407,238; F. Gabrera
Escribano, et al. Tetrahedron Letters, Vol. 29, No. 46, pp.
6001-6004, 1988; Org. Biomol. Chem., 2006, 4, 4158-4164; WO
2003/026666.
##STR00097##
[0221] Precursors R.sub.3H can be purchased from suppliers as
exampled earlier, or synthesized from commercially available
precursors using established protocols. For example, as illustrated
in Scheme 3, substituted N-(mercaptophenyl)carboxamide (IVa) are
readily available from the reaction of an aminobenzenethiol with a
carboxylic acid or its derivatives such as acyl chloride, acid
anhydride or ester.
##STR00098##
[0222] Alternatively, substituted mercapto-N-benzamide (IVb) can be
prepared by mercaptobenzoic acid, which is protected by appropriate
group, with the corresponding amines as was shown in Scheme 4.
##STR00099##
[0223] The preparation of the compounds of formula (I) or formula
(II) in this invention can be carried out by methods known in the
art (e.g., J. Med. Chem. 1996, 39, 4354-4357; J. Med. Chem. 2004,
47, 600-611; J. Med. Chem. 2004, 47, 6283-6291; J. Med. Chem. 2005,
48, 1717-1720; J. Med. Chem. 2005, 48, 5570-5579; U.S. Pat. No.
6,340,683 B1; JOC, 2004, 29, 7809, 7815.)
##STR00100##
[0224] Scheme 5 illustrated the synthesis method for compounds with
alkyl or aryl as R.sub.2. The 6-alkyl or aryl substituted
dichloro-triazine (b) may be synthesized by the methods known in
the art (e.g., J. Med. Chem. 1999, 42, 805-818 and J. Med. Chem.
2004, 47, 600-611) from cyanuric chloride (a) and Grignard
reagents. The monochloro-triazine (c) can be formed from the
reaction of a 6-alkyl or aryl substituted dichloro-triazine (b)
with heterocyclic amine, which can be converted to triazine
derivatives of formula (I) or formula (II) by reaction with
HR.sub.3. Alternatively, the dichloro-triazine (b) can be converted
to monochloro-triazine (d) by reacting with HR.sub.2, which also
can be converted to triazine derivatives of formula (I) or formula
(II) by reacting with a heterocyclic amine.
[0225] Similarly compounds with alkyl or aryl as R.sub.3 can be
prepared eith the same method as illustrated in Scheme 6.
##STR00101##
##STR00102##
[0226] As shown in Scheme 7, the triazine derivative can also be
synthesized by the reaction of cyanuric chloride with a sequence of
heterocyclic amines and HR.sub.2 to give
2,4-disubstituted-6-chloro-1,3,5-triazines. The displacement of the
last chlorine by HR.sub.3 can be achieved by increasing the
temperature, affording the trisubstituted-1,3,5-triazines of
formula (I) or formula (II). Alternative sequence can also be used
to make triazine derivatives as illustrated in Scheme 7.
##STR00103##
[0227] Furthermore, the triazine derivative can be modified to
added or remove substituents. For example, a substituted
thio-N-benzamide (Ic) can be prepared for the corresponding acid
(Ib) by known methods as shown in Scheme 8.
##STR00104##
[0228] The reaction is preferably conducted in the presence of an
inert solvent. There is no particular restriction on the nature of
the solvent to be employed, provided that it has no adverse effect
on the reaction or on the reagents involved and that it can
dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; halogenated hydrocarbons,
especially aromatic and aliphatic hydrocarbons, such as methylene
chloride, chloroform, carbon tetrachloride, dichloroethane,
chlorobenzene and the dichlorobenzenes; esters, such as ethyl
formate, ethyl acetate, propyl acetate, butyl acetate and diethyl
carbonate; ethers, such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane. dimethoxyethane and diethylene glycol
dimethyl ether; ketones, such as acetone, methyl ethyl ketone,
methyl isobutyl ketone, isophorone and cyclohexanone; nitro
compounds, which may be nitroalkanes or nitroaranes, such as
nitroethane and nitrobenzene; nitriles, such as acetonitrile and
isobutyronitrile; amides, which may be fatty acid amides, such as
formamide, dimethylformamide, dimethylacetamide and
hexamethylphosphoric triamide; and sulphoxides, such as dimethyl
sulphoxide and sulpholane.
[0229] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. In general, we find it convenient to carry out
the reaction at a temperature of from -50.degree. C. to 100.degree.
C.
[0230] The present invention provides compositions of matter that
are formulations of one or more active drugs and a
pharmaceutically-acceptable carrier. In this regard, the invention
provides a composition for administration to a mammalian subject,
which may include a compound of formula (I) or formula (II), or its
pharmaceutically acceptable salts.
[0231] Pharmaceutically acceptable salts of the compounds of this
invention include those derived from pharmaceutically acceptable
inorganic and organic acids and bases. Examples of suitable acid
salts include acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptanoate, glycerophosphate, glycolate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate, succinate,
sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other
acids, such as oxalic, while not in themselves pharmaceutically
acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
[0232] Salts derived from appropriate bases include alkali metal
(e.g., sodium and potassium), alkaline earth metal (e.g.,
magnesium), ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization.
[0233] The compositions of the present invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally,
intraperitoneally or intravenously.
[0234] The pharmaceutically acceptable compositions of this
invention may be orally administered in any orally acceptable
dosage form including, but not limited to, capsules, tablets,
troches, elixirs, suspensions, syrups, wafers, chewing gums,
aqueous suspensions or solutions.
[0235] The oral compositions may contain additional ingredients
such as: a binder such as microcrystalline cellulose, gum
tragacanth or gelatin; an excipient such as starch or lactose, a
disintegrating agent such as alginic acid, corn starch and the
like; a lubricant such as magnesium stearate; a glidant such as
colloidal silicon dioxide; and a sweetening agent such as sucrose
or saccharin or flavoring agent such as peppermint, methyl
salicylate, or orange flavoring. When the dosage unit form is a
capsule, it may additionally contain a liquid carrier such as a
fatty oil. Other dosage unit forms may contain other various
materials which modify the physical form of the dosage unit, such
as, for example, a coating. Thus, tablets or pills may be coated
with sugar, shellac, or other enteric coating agents. A syrup may
contain, in addition to the active ingredients, sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors. Materials used in preparing these various compositions
should be pharmaceutically or veterinarally pure and non-toxic in
the amounts used.
[0236] For the purposes of parenteral therapeutic administration,
the active ingredient may be incorporated into a solution or
suspension. The solutions or suspensions may also include the
following components: a sterile diluent such as water for
injection, saline solution, fixed oils, polyethylene glycols,
glycerine, propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfate; chelating
agents such as ethylenediaminetetraacetic acid; buffers such as
acetates, citrates or phosphates and agents for the adjustment of
tonicity such as sodium chloride or dextrose. The parenteral
preparation can be enclosed in ampoules, disposable syringes or
multiple dose vials made of glass or plastic.
[0237] The pharmaceutical forms suitable for injectable use include
sterile solutions, dispersions, emulsions, and sterile powders. The
final form should be stable under conditions of manufacture and
storage. Furthermore, the final pharmaceutical form should be
protected against contamination and should, therefore, be able to
inhibit the growth of microorganisms such as bacteria or fungi. A
single intravenous or intraperitoneal dose can be administered.
Alternatively, a slow long-term infusion or multiple short-term
daily infusions may be utilized, typically lasting from 1 to 8
days. Alternate day dosing or dosing once every several days may
also be utilized.
[0238] Sterile, injectable solutions may be prepared by
incorporating a compound in the required amount into one or more
appropriate solvents to which other ingredients, listed above or
known to those skilled in the art, may be added as required.
Sterile injectable solutions may be prepared by incorporating the
compound in the required amount in the appropriate solvent with
various other ingredients as required. Sterilizing procedures, such
as filtration, may then follow. Typically, dispersions are made by
incorporating the compound into a sterile vehicle which also
contains the dispersion medium and the required other ingredients
as indicated above. In the case of a sterile powder, the preferred
methods include vacuum drying or freeze drying to which any
required ingredients are added.
[0239] Suitable pharmaceutical carriers include sterile water;
saline, dextrose; dextrose in water or saline; condensation
products of castor oil and ethylene oxide combining about 30 to
about 35 moles of ethylene oxide per mole of castor oil; liquid
acid; lower alkanols; oils such as corn oil; peanut oil, sesame oil
and the like, with emulsifiers such as mono- or di-glyceride of a
fatty acid, or a phosphatide, e.g., lecithin, and the like;
glycols; polyalkylene glycols; aqueous media in the presence of a
suspending agent, for example, sodium carboxymethylcellulose;
sodium alginate; poly(vinylpyrolidone); and the like, alone, or
with suitable dispensing agents such as lecithin; polyoxyethylene
stearate; and the like. The carrier may also contain adjuvants such
as preserving stabilizing, wetting, emulsifying agents and the like
together with the penetration enhancer. In all cases, the final
form, as noted, must be sterile and should also be able to pass
readily through an injection device such as a hollow needle. The
proper viscosity may be achieved and maintained by the proper
choice of solvents or excipients. Moreover, the use of molecular or
particulate coatings such as lecithin, the proper selection of
particle size in dispersions, or the use of materials with
surfactant properties may be utilized.
[0240] In accordance with the invention, there are provided
compositions containing triazine derivatives and methods useful for
the in vivo delivery of triazine derivatives in the form of
nanoparticles, which are suitable for any of the aforesaid routes
of administration.
[0241] U.S. Pat. Nos. 5,916,596, 6,506,405 and 6,537,579 teach the
preparation of nanoparticles from the biocompatible polymers, such
as albumin. Thus, in accordance with the present invention, there
are provided methods for the formation of nanoparticles of the
present invention by a solvent evaporation technique from an
oil-in-water emulsion prepared under conditions of high shear
forces (e.g., sonication, high pressure homogenization, or the
like).
[0242] Alternatively, the pharmaceutically acceptable compositions
of this invention may be administered in the form of suppositories
for rectal administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that is solid at
room temperature but liquid at rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0243] The pharmaceutically acceptable compositions of this
invention may also be administered topically, especially when the
target of treatment includes areas or organs readily accessible by
topical application, including diseases of the eye, the skin, or
the lower intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0244] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0245] For topical applications, the pharmaceutically acceptable
compositions may be formulated in a suitable ointment containing
the active component suspended or dissolved in one or more
carriers. Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutically acceptable compositions can be
formulated in a suitable lotion or cream containing the active
components suspended or dissolved in one or more pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0246] For ophthalmic use, the pharmaceutically acceptable
compositions may be formulated as micronized suspensions in
isotonic, pH adjusted sterile saline, or, preferably, as solutions
in isotonic, pH adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, for
ophthalmic uses, the pharmaceutically acceptable compositions may
be formulated in an ointment such as petrolatum.
[0247] The pharmaceutically acceptable compositions of this
invention may also be administered by nasal aerosol or inhalation.
Such compositions are prepared according to techniques well-known
in the art of pharmaceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or dispersing
agents.
[0248] Most preferably, the pharmaceutically acceptable
compositions of this invention are formulated for oral
administration.
[0249] In accordance with the invention, the compounds of the
invention may be used to treat diseases associated with cellular
proliferation or hyperproliferation, such as cancers which include
but are not limited to tumors of the nasal cavity, paranasal
sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx,
salivary glands, and paragangliomas. The compounds of the invention
may also be used to treat cancers of the liver and biliary tree
(particularly hepatocellular carcinoma), intestinal cancers,
particularly colorectal cancer, ovarian cancer, small cell and
non-small cell lung cancer, breast cancer, sarcomas (including
fibrosarcoma, malignant fibrous histiocytoma, embryonal
rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma,
osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part
sarcoma), neoplasms of the central nervous systems (particularly
brain cancer), and lymphomas (including Hodgkin's lymphoma,
lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated
lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large
cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell
lymphoma).
[0250] The compounds and methods of the present invention, either
when administered alone or in combination with other agents (e.g.,
chemotherapeutic agents or protein therapeutic agents described
below) are also useful in treating a variety of disorders,
including but not limited to, for example: stroke, cardiovascular
disease, myocardial infarction, congestive heart failure,
cardiomyopathy, myocarditis, ischemic heart disease, coronary
artery disease, cardiogenic shock, vascular shock, pulmonary
hypertension, pulmonary edema (including cardiogenic pulmonary
edema), pleural effusions, rheumatoid arthritis, diabetic
retinopathy, retinitis pigmentosa, and retinopathies, including
diabetic retinopathy and retinopathy of prematurity, inflammatory
diseases, restenosis, asthma, acute or adult respiratory distress
syndrome (ARDS), lupus, vascular leakage, protection from ischemic
or reperfusion injury such as ischemic or reperfusion injury
incurred during organ transplantation, transplantation tolerance
induction; ischemic or reperfusion injury following angioplasty;
arthritis (such as rheumatoid arthritis, psoriatic arthritis or
osteoarthritis); multiple sclerosis; inflammatory bowel disease,
including ulcerative colitis and Crohn's disease; lupus (systemic
lupus crythematosis); graft vs. host diseases; T-cell mediated
hypersensitivity diseases, including contact hypersensitivity,
delayed-type hypersensitivity, and gluten-sensitive enteropathy
(Celiac disease); Type 1 diabetes; psoriasis; contact dermatitis
(including that due to poison ivy); Hashimoto's thyroiditis;
Sjogren's syndrome; Autoimmune Hyperthyroidism, such as Graves'
disease; Addison's disease (autoimmune disease of the adrenal
glands); autoimmune polyglandular disease (also known as autoimmune
polyglandular syndrome); autoimmune alopecia; pernicious anemia;
vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome;
other autoimmune diseases; cancers, including those where kineses
such as Src-family kineses are activated or overexpressed, such as
colon carcinoma and thymoma, or cancers where kinase activity
facilitates tumor growth or survival; glomerulonephritis, serum
sickness; uticaria; allergic diseases such as respiratory allergies
(asthma, hayfever, allergic rhinitis) or skin allergies; mycosis
fungoides; acute inflammatory responses (such as acute or adult
respiratory distress syndrome and ischemialreperfusion injury);
dermatomyositis; alopecia greata; chronic actinic dermatitis;
eczema; Behcet's disease; Pustulosis palmoplanteris; Pyoderma
gangrenum; Sezary's syndrome; atopic dermatitis; systemic
schlerosis; morphea; peripheral limb ischemia and ischemic limb
disease; bone disease such as osteoporosis, osteomalacia,
hyperparathyroidism, Paget's disease, and renal osteodystrophy;
vascular leak syndromes, including vascular leak syndromes induced
by chemotherapies or immunomodulators such as IL-2; spinal cord and
brain injury or trauma; glaucoma; retinal diseases, including
macular degeneration; vitreoretinal disease; pancreatitis;
vasculatides, including vasculitis, Kawasaki disease,
thromboangiitis obliterans, Wegener s granulomatosis, and Behcet's
disease; scleroderma; preeclampsia; thalassemia; Kaposi's sarcoma;
von Hippel Lindau disease; and the like.
[0251] In accordance with the invention, the compounds of the
invention may be used to treat diseases associated with undesired
cellular proliferation or hyperproliferation comprising identifying
the mammal afflicted with said disease or condition and
administering to said afflicted mammal a composition comprising the
compound of formula 1, wherein the disease or condition is
associated with a kinase.
[0252] In accordance with the invention, the compounds of the
invention may be used to treat diseases associated with undesired
cellular proliferation or hyperproliferation comprising identifying
the mammal afflicted with said disease or condition and
administering to said afflicted mammal a composition comprising the
compound of formula (I) or formula (II), wherein the disease or
condition is associated with a tyrosine kinase.
[0253] In accordance with the invention, the compounds of the
invention may be used to treat diseases associated with undesired
cellular proliferation or hyperproliferation comprising identifying
the mammal afflicted with said disease or condition and
administering to said afflicted mammal a composition comprising the
compound of formula (I) or formula (II), wherein the disease or
condition is associated with the kinase that is a serine kinase or
a threonine kinase.
[0254] In accordance with the invention, the compounds of the
invention may be used to treat diseases associated with undesired
cellular proliferation or hyperproliferation comprising identifying
the mammal afflicted with said disease or condition and
administering to said afflicted mammal a composition comprising the
compound of formula (I) or formula (II), wherein the disease or
condition is associated with the kinase that is a Src family
kinase.
[0255] The invention also provides methods of treating a mammal
afflicted with the above diseases and conditions. The amount of the
compounds of the present invention that may be combined with the
carrier materials to produce a composition in a single dosage form
will vary depending upon the host treated, the particular mode of
administration. Preferably, the compositions should be formulated
so that a dosage of between 0.01-100 mg/kg body weight/day of the
inhibitor can be administered to a patient receiving these
compositions.
[0256] In one aspect, the invention compounds are administered in
combination with chemotherapeutic agent, an anti-inflammatory
agent, antihistamines, chemotherapeutic agent, immunomodulator,
therapeutic antibody or a protein kinase inhibitor, e.g., a
tyrosine kinase inhibitor, to a subject in need of such
treatment.
[0257] The method includes administering one or more of the
inventive compounds to the afflicted mammal. The method may further
include the administration of a second active agent, such as a
cytotoxic agent, including alkylating agents, tumor necrosis
factors, intercalators, microtubulin inhibitors, and topoisomerase
inhibitors. The second active agent may be co-administered in the
same composition or in a second composition. Examples of suitable
second active agents include, but are not limited to, a cytotoxic
drug such as Acivicin; Aclarubicin; Acodazole Hydrochloride;
AcrQnine; Adozelesin; Aldesleukin; Altretamine; Ambomycin;
Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole;
Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa;
Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene
Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate;
Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone;
Caracemide; Carbetimer; Carboplatin; Cannustine; Carubicin
Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin;
Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide;
Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride;
Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate;
Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride;
Droloxifene; Droloxifene Citrate; Dromostanolone Propionate;
Duazomycin; Edatrexate; Eflomithine Hydrochloride; Elsamitrucin;
Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride;
Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine
Phosphate Sodium; Etanidazole; Ethiodized Oil 131; Etoposide;
Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine;
Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil;
Fluorocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine;
Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin
Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a;
Interferon Alfa-2b; Interferon Alfa-n1; Interferon Alfa-n3;
Interferon Beta-.quadrature.a; Interferon Gamma-Ib; Iproplatin;
Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide
Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine;
Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine
Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan;
Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium;
Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin;
Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone
Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin;
Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin;
Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman;
Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane;
Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine
Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin;
Riboprine; Rogletimide; Safmgol; Safingol Hydrochloride; Semustine;
Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium
Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin;
Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin;
Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone
Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone;
Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine;
Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate;
Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate;
Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa;
Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate;
Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate
Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine
Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and
Zorubicin Hydrochloride.
[0258] In accordance with the invention, the compounds and
compositions may be used at sub-cytotoxic levels in combination
with other agents in order to achieve highly selective activity in
the treatment of non-neoplastic disorders, such as heart disease,
stroke and neurodegenerative diseases (Whitesell et al., Curr
Cancer Drug Targets (2003), 3(5), 349-58).
[0259] The exemplary therapeutical agents that may be administered
in combination with invention compounds include EGFR inhibitors,
such as gefitinib, erlotinib, and cetuximab. Her2 inhibitors
include canertinib, EKB-569, and GW-572016. Also included are Src
inhibitors, dasatinib, as well as Casodex (bicalutamide),
Tamoxifen, MEK-1 kinase inhibitors, MARK kinase inhibitors, PI3
inhibitors, and PDGF inhibitors, such as imatinib, Hsp90
inhibitors, such as 17-AAG and 17-DMAG. Also included are
anti-angiogenic and antivascular agents which, by interrupting
blood flow to solid tumors, render cancer cells quiescent by
depriving them of nutrition. Castration, which also renders
androgen dependent carcinomas non-proliferative, may also be
utilized. Also included are IGF1R inhibitors, inhibitors of
non-receptor and receptor tyrosine kineses, and inhibitors of
integrin.
[0260] The pharmaceutical composition and method of the present
invention may further combine other protein therapeutic agents such
as cytokines, immunomodulatory agents and antibodies. As used
herein the term "cytokine" encompasses chemokines, interleukins,
lymphokines, monokines, colony stimulating factors, and receptor
associated proteins, and functional fragments thereof. As used
herein, the term "functional fragment" refers to a polypeptide or
peptide which possesses biological function or activity that is
identified through a defined functional assay. The cytokines
include endothelial monocyte activating polypeptide II (EMAP-II),
granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF),
macrophage-CSF (M-CSF), IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-12,
and IL-13, interferons, and the like and which is associated with a
particular biologic, morphologic, or phenotypic alteration in a
cell or cell mechanism.
[0261] Other therapeutic agents for the combinatory therapy include
cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as
ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2,
anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking
the interaction between CD40 and gp39, such as antibodies specific
for CD40 and for gpn39 (i.e., CD154), fusion proteins constructed
from CD40 and gp39 (CD401g and CD8gp39), inhibitors, such as
nuclear translocation inhibitors, of NF-kappa B function, such as
deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as
HM:G CoA reductase inhibitors (lovastatin and simvastatin),
non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and
cyclooxygenase inhibitors such as rofecoxib, steroids such as
prednisone or dexamethasone, gold compounds, antiproliferative
agents such as methotrexate, FK506 (tacrolimus, Prograf),
mycophenolate mofetil, cytotoxic drugs such as azathioprine and
cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF
antibodies or soluble TNF receptor, and rapamycin (sirolimus or
Rapamune) or derivatives thereof.
[0262] When other therapeutic agents are employed in combination
with the compounds of the present invention they may be used for
example in amounts as noted in the Physician Desk Reference (PDR)
or as otherwise determined by one having ordinary skill in the
art.
EXAMPLES
[0263] The following examples are provided to further illustrate
the present invention but, of course, should not be construed as in
any way limiting its scope.
[0264] All experiments were performed under anhydrous conditions
(i.e. dry solvents) in an atmosphere of argon, except where stated,
using oven-dried apparatus and employing standard techniques in
handling air-sensitive materials. Aqueous solutions of sodium
bicarbonate (NaHCO.sub.3) and sodium chloride (brine) were
saturated.
[0265] Analytical thin layer chromatography (TLC) was carried out
on Merck Kiesel gel 60 F254 plates with visualization by
ultraviolet and/or anisaldehyde, potassium permanganate or
phosphomolybdic acid dips.
[0266] NMR spectra: 1H Nuclear magnetic resonance spectra were
recorded at 400 MHz. Data are presented as follows: chemical shift,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,
qn=quintet, dd=doublet of doublets, m=multiplet, bs=broad singlet),
coupling constant (J/Hz) and integration. Coupling constants were
taken and calculated directly from the spectra and are
uncorrected.
[0267] Low resolution mass spectra: Electrospray (ES+) ionization
was used. The protonated parent ion (M+H) or parent sodium ion
(M+Na) or fragment of highest mass is quoted. Analytical gradient
consisted of 10% ACN in water ramping up to 100% ACN over 5 minutes
unless otherwise stated.
[0268] High performance liquid chromatography (HPLC) was use to
analyze the purity of triazine derivatives. HPLC was performed on a
Phenomenex Synergi Polar-RP, 4u, 80A, 150.times.4.6 mm column using
a vShimadzusystem equipted with SPD-M10A Phosphodiode Array
Detector. Mobile phase A was water and mobile phase B was
acetonitrile with a gradient from 20% to 80% B over 60 minutes and
re-equilibrate at A/B (80:20) for 10 minutes. UV detection was at
220 and 54 nm.
Example 1
##STR00105##
[0270] To a solution of 4-aminothiophenol (6.00 g, 47.93 mmol) and
pyridine (5.3 mL, 65.53 mmol) in THF (100 mL) at -5.degree. C. was
added a solution of cyclopropanecarbonyl chloride (3.00 mL, 32.77
mmol) in THF (100 mL) drop wise. The reaction was stirred from
0.degree. C. to room temperature for overnight, diluted with EtOAc
(100 mL), washed with 1 N HCl (100 mL.times.5), dried over
Na.sub.2SO.sub.4, concentrated, and dried under vacuum to yield the
compound 1 as an off-white solid (6.01 g, 95%). Rf 0.50 (50%
EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6) .delta. 10.12 (s, 1H),
7.45 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz, 2H), 5.18 (s, 1H), 1.72
(m, 1H), 0.78 (m, 4H); ESI-MS: calcd for (C.sub.10H.sub.11NOS) 193.
found 194 (MH+).
Example 2
##STR00106##
[0272] To a solution of cyanuric chloride (300 mg, 1.63 mmol) in
THF (20 mL) was added a solution of 3-amino-5-methylpyrazole (158
mg, 1.63 mmol) and DIPEA (0.28 mL, 1.63 mmol) in THF (15 mL)
dropwise at -10.degree. C. After addition, the mixture was stirred
at -10.degree. C. for 30 more minutes. TLC was checked and the
starting materials were consumed. In a separate flask, compound 1
(315 mg, 1.63 mmol) and DIPEA (0.28 mL, 1.63 mmol) was dissolved in
THF (15 mL) and added to the above reaction flak drowise at
0.degree. C. The mixture was stirred at room temperature overnight.
Methyl piperazine (0.70 mL, 6.30 mmol) and DIPEA (0.57 mL, 3.26
mmol) was added to the reaction flask and the mixture was stirred
at 60.degree. C. for 2 hours. After cool to room temperature,
saturated NaHCO.sub.3 in water was added to the flask and the
mixture was extracted by ethyl acetate two times. The combined
organic was washed by brine, dried over sodium sulfate and
concentrated. The resulting crude product was purified by flash
column chromatography on silica gel using EtOAc/DCM/MeOH (7N NH3):
100/25/7 v/v/v as eluent to provide compound 2 as white solids (120
mg, 16%). 1H NMR (500 MHz, DMSO-d6) .delta. 11.71 (br, 1H), 10.43
(br, 1H), 9.50 (br, 1H), 7.72 (br, 2H), 7.48 (d, J=8.5 Hz, 2H),
5.30 (br, 1H), 3.67 (br, 4H), 2.30 (br, 4H), 2.18-1.95 (s, s, 6H),
1.80 (t, J=6.2 Hz, 1H), 0.81 (d, J=6.2 Hz, 4H); ESI-MS: calcd for
(C.sub.22H.sub.27N.sub.9OS) 465. found 466 (MH+). HPLC: retention
time: 37.35 min. purity: 98%.
Example 3
##STR00107##
[0274] A solution of ethylmagnesium bromide in ether (3M, 15 ml, 45
mmole) was added dropwise to a stirred solution of cyanuric
chloride (5.64 g, 30.58 mmole) in anhydrous dichloromethane at
-10.degree. C. After the addition was complete, the reaction
mixture was stirred at -5.degree. C. for 1 h, after which time
water was added dropwise at a rate such that the temperature of the
reaction stayed below 10.degree. C. After warming to room
temperature, the reaction mixture was diluted with additional water
and methylene chloride and passed through a pad of cilite. The
organic layer was dried and evaporated to give
2,4-dichloro-6-ethyl-1,3,5-triazine of compound 3 as yellow liquid,
which solidified after storied in the refrigerator (5.20 g, 96%).
1H NMR (500 MHz, CDCl.sub.3) .delta. 2.95 (q, J=7.5 Hz. 2H), 1.38
(t, J=7.5 Hz. 3H).
Example 4
##STR00108##
[0276] To a solution of compound 3 (163 mg, 0.90 mmol) in THF (10
mL) was added a solution of 3-amino-5-methylpyrazole (87 mg, 0.90
mmol) and DIPEA (0.16 mL, 0.90 mmol) in THF (5 mL) dropwise at
0.degree. C. After addition, the mixture was stirred at 0.degree.
C. for additional 60 minutes. TLC was checked and the starting
materials were consumed. A solution of compound 1 (303 mg, 1.56
mmol) and DIPEA (0.26 mL, 1.50 mmol) in THF (5 mL) was added to the
above reaction flak at room temperature. The mixture was stirred at
70.degree. C. for overnight. After cooling to room temperature,
saturated NaHCO3 in water was added to the flask and the mixture
was extracted by ethyl acetate (3.times.). The combined organic was
washed by brine, dried over sodium sulfate and concentrated. The
resulting crude product was purified by flash column chromatography
on silica gel using DCM/MeOH (7N NH.sub.3): 00/3 v/v as eluent to
provide compound 4 as white solids (150 mg, 42%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.80 (br, 1H), 10.45 (br, 1H), 10.18 (br, 1H),
7.75 (d, J=9.2 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 5.24 (br, 1H), 2.51
(q, J=7.6 Hz, 2H), 1.93 (s, 3H), 1.80 (m, 1H), 1.16 (t, J=7.6 Hz,
3H), 0.80 (d, J=6.0 Hz, 4H); ESI-MS: calcd for
(C.sub.19H.sub.21N.sub.7OS) 395. found 396 (MH+). HPLC: retention
time: 21.97 min. purity: 98%.
Example 5
##STR00109##
[0278] A solution of cyclopropylmagnesium bromide in THF (0.5 M, 25
ml, 12.5 mmol) was added dropwise to a stirred solution of cyanuric
chloride (1.8 g, 10.00 mmol) in anhydrous dichloromethane at -10 to
0.degree. C. After the addition was complete, the reaction mixture
was stirred at 0.degree. C. for 3 h, Water was added dropwise to
the reaction mixture at a rate such that the temperature of the
reaction stayed below 10.degree. C. After warming to room
temperature, the reaction mixture was diluted with additional water
and methylene chloride and passed through a pad of cilite. The
organic layer was dried and evaporated to give
2,4-dichloro-6-cyclopropyl-1,3,5-triazine of 5 as yellow liquid,
which solidified after storied in the refrigerator (1.8 g, 95%). 1H
NMR (400 MHz, CDCl.sub.3) .delta. 2.20 (m, 1H), 1.38 (m, 2H), 1.32
(m, 2H).
Example 6
##STR00110##
[0280] To a solution of compound 5 (195 mg, 1.03 mmol) in THF (10
mL) was added a solution of compound 1 (237 mg, 1.22 mmol) and
DIPEA (0.17 mL, 1.00 mmol) in THF (5 mL) dropwise at 0.degree. C.
After addition, the mixture was stirred at room temperature for
overnight. A solution 3-amino-5-methylpyrazole (146 mg, 1.50 mmol)
and DIPEA (0.26 mL, 1.50 mmol) in THF (5 mL) was added to the above
reaction flak at room temperature. The mixture was stirred at
60.degree. C. for 2 hours. After cooling to room temperature,
saturated NaHCO.degree. in water was added to the flask and the
mixture was extracted by ethyl acetate (3.times.). The combined
organic was washed by brine, dried over sodium sulfate and
concentrated. The resulting crude product was purified by flash
column chromatography on silica gel using DCM/MeOH (7N NH.sub.3):
100/3 v/v as eluent to provide compound 6 as white solids (90 mg,
21%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.80 (br, 1H), 10.43 (br,
1H), 10.06 (br, 1H), 7.75 (m, 2H), 7.48 (d, J=8.8 Hz, 2H), 5.25
(br, 1H), 1.93 (s, 3H), 1.80 (m, 2H), 0.96 (m, 4H), 0.80 (d, J=6.0
Hz, 4H); ESI-MS: calcd for (C.sub.20H.sub.21N.sub.7OS) 407. found
408 (MH+). HPLC: retention time: 25.43 min. purity: 93%.
Example 7
##STR00111##
[0282] A solution of compound 1 (1.85 g, 9.57 mmol) and DIPEA (1.70
mL, 9.76 mmol) in THF (75 mL) was added dropwise to a stirred
solution of cyanuric chloride (1.90 g, 10.30 mmol) in THF (50 mL)
at 0.degree. C. After the addition was complete, the reaction
mixture was stirred at 10 to 20.degree. C. for 30 more minute.
Saturated ammonium chloride in water was added to the reaction
mixture and the mixture was extracted with ethyl acetate
(1.times.). The organic layer was washed by brine, dried
(Na.sub.2SO.sub.4) and concentrated to give compound 7 as white
solids (3.22 g, 99% yield). 1H NMR (400 MHz, DMSO-d6): .delta.
11.12 (s, 1H), 7.69 (d, t=8.4 Hz, 2H), 7.45 (d, t=8.4 Hz, 2H), 1.80
(m, 1H), 0.81 (m, 4H). ESI-MS: calcd for
(C.sub.13H.sub.10Cl.sub.2N.sub.4OS) 340. found 341 (MH+).
Example 8
##STR00112##
[0284] To a solution of compound 7 (180 mg, 0.53 mmol) in THF (10
mL) was added a solution of compound 3-amino-1,2,4-triazole (38 mg,
0.46 mmol) and DIPEA (0.08 mL, 0.46 mmol) in THF (5 mL) dropwise at
0.degree. C. After addition, the mixture was stirred at 30.degree.
C. for overnight. A 1-methylpiperazine (0.10 ml, 0.90 mmol) and
DIPEA (0.08 mL, 0.46 mmol) was added to the above reaction flak at
room temperature. The mixture was stirred at 60.degree. C. for 3
hours. After cooling to room temperature, saturated NaHCO.sub.3 in
water was added to the flask and the mixture was extracted by ethyl
acetate (3.times.). The combined organic was washed by brine, dried
over sodium sulfate and concentrated. The resulting crude product
was purified by flash column chromatography on silica gel using
DCM/MeOH (2N NH3): 100/6 v/v as eluent to provide compound 8 as
white solids (30 mg, 15%). 1H NMR (400 MHz, DMSO-d6) .delta. 10.41
(s, 1H), 9.50 (br, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz,
2H), 7.10 (br, 1H), 4.60 (br, 2H), 3.60 (br, 2H), 3.00 (br, 4H),
2.80 (br, 3H), 1.80 (m, 1H), 0.81 (m, 4H); ESI-MS: calcd for
(C.sub.20H.sub.24N.sub.10OS) 452. found 453 (MH+). HPLC: retention
time: 9.61 min. purity: 79%.
Example 9
##STR00113##
[0286] To a solution of compound 7 (180 mg, 0.53 mmol) in THF (10
mL) was added a solution of compound 2-amino-benzimidazole (61 mg,
0.46 mmol) and DIPEA (0.08 mL, 0.46 mmol) in THF (5 mL) dropwise at
0.degree. C. After addition, the mixture was stirred at 30.degree.
C. for overnight. A 1-methylpiperazine (0.10 ml, 0.90 mmol) and
DIPEA (0.08 mL, 0.46 mmol) was added to the above reaction flak at
room temperature. The mixture was stirred at 60.degree. C. for 3
hours. After cooling to room temperature, saturated NaHCO3 in water
was added to the flask and the mixture was extracted by ethyl
acetate (3.times.). The combined organic was washed by brine, dried
over sodium sulfate and concentrated. The resulting crude product
was purified by flash column chromatography on silica gel using
DCM/MeOH (2N NH.sub.3): 100/3 v/v as eluent to provide compound 9
as white solids (60 mg, 26%). 1H NMR (400 MHz, DMSO-d6) .delta.
10.45 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.57 (m, 3H), 7.30 (br, 2H),
7.07 (d, J=9.2 Hz, 1H), 7.02 (t, J=8.4 Hz, 1H), 6.73 (t, J=8.4 Hz,
1H), 3.76 (br, 4H), 2.40 (br, 4H), 2.21 (br, 3H), 1.82 (m, 1H),
0.84 (m, 4H); ESI-MS: calcd for (C.sub.25H.sub.27N.sub.9OS) 501.
found 502 (MH+). HPLC: retention time: 10.56 min. purity: 92%.
Example 10
##STR00114##
[0288] To a solution of compound 7 (180 mg, 0.53 mmol) in THF (10
mL) was added a solution of compound 2-amino-5-methylthiazole (52
mg, 0.46 mmol) and DIPEA (0.08 mL, 0.46 mmol) in THF (5 mL)
dropwise at 0.degree. C. After addition, the mixture was stirred at
30.degree. C. for overnight. A 1-methylpiperazine (0.10 ml, 0.90
mmol) and DIPEA (0.08 mL, 0.46 mmol) was added to the above
reaction flak at room temperature. The mixture was stirred at
60.degree. C. for 3 hours. After cooling to room temperature,
saturated NaHCO.sub.3 in water was added to the flask and the
mixture was extracted by ethyl acetate (3.times.). The combined
organic was washed by brine, dried over sodium sulfate and
concentrated. The resulting crude product was purified by flash
column chromatography on silica gel using DCM/MeOH (2N NH.sub.3):
100/5 v/v as eluent to provide compound 10 as white solids (25 mg,
11%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.15 (br, 1H), 10.40 (s,
1H), 7.69 (d, J=8.8 Hz, 2H), 7.50 (m, 2H), 7.00 (br, 1H), 3.76 (br,
4H), 2.33 (br, 4H), 2.18-2.00 (multiple s, 6H), 1.78 (m, 1H), 0.81
(m, 4H); ESI-MS: calcd for (C.sub.22H.sub.26N.sub.8OS.sub.2) 482.
found 483 (MH+). HPLC: retention time: 15.51 min. purity: 96%.
Example 11
##STR00115##
[0290] To a solution of compound 7 (180 mg, 0.53 mmol) in THF (10
mL) was added a solution of compound 2-amino-1,3,4-thiadiazole (46
mg, 0.46 mmol) and DIPEA (0.08 mL, 0.46 mmol) in THF (5 mL)
dropwise at 0.degree. C. After addition, the mixture was stirred at
30.degree. C. for overnight. A 1-methylpiperazine (0.10 ml, 0.90
mmol) and DIPEA (0.08 mL, 0.46 mmol) was added to the above
reaction flak at room temperature. The mixture was stirred at
60.degree. C. for 3 hours. After cooling to room temperature,
saturated NaHCO.sub.3 in water was added to the flask and the
mixture was extracted by ethyl acetate (3.times.). The combined
organic was washed by brine, dried over sodium sulfate and
concentrated. The resulting crude product was purified by flash
column chromatography on silica gel using DCM/MeOH (2N NH.sub.3):
100/5 v/v as eluent to provide compound 11 as white solids (20 mg,
9%). 1H NMR (400 MHz, DMSO-d6) .delta. 12.00 (br, 1H), 10.37 (s,
1H), 9.00 (br, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H),
3.76-3.50 (m, 4H), 2.40-2.20 (m, 4H), 2.16 (s, 3H), 1.78 (m, 1H),
0.81 (m, 4H); ESI-MS: calcd for (C.sub.20H.sub.23N.sub.9OS.sub.2)
469. found 470 (MH+). HPLC: retention time: 11.32 min. purity:
85%.
Example 12
##STR00116##
[0292] To a solution of compound 7 (200 mg, 0.59 mmol) in THF (10
mL) was added a solution of compound 3-amino-5-methylpyrazole (57
mg, 0.59 mmol) and DIPEA (0.10 mL, 0.59 mmol) in THF (3 mL)
dropwise at 0.degree. C. After addition, the mixture was stirred at
0.degree. C. for 2 hours. A solution of 1-(4-pyridine)piperazine
(110 ml, 0.67 mmol) and DIPEA (0.26 mL, 1.50 mmol) in THF (5 mL)
was added to the above reaction flak at room temperature. The
mixture was stirred at room temperature for overnight (white
precipitation formed). Ethyl acetate and saturated NaHCO.sub.3 in
water was added to the flask. The solids was filtered and washed by
ethyl acetate. The solids was dissolved in methanol and
dichloromethane and mixed with silica gel. After removal of
solvents, the sample was loaded on a silica gel column and eluted
by DCM/MeOH (2N NH.sub.3): 100/5 v/v to provide compound 12 as
white solids (60 mg, 19%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.85
(br, 1H), 10.41 (s, 1H), 9.59 (br, 1H), 8.15 (br, 2H), 7.75 (m,
2H), 7.49 (d, J=8.4 Hz, 2H), 6.83 (b, 2H), 5.25 (br, 1H), 3.78 (m,
4H), 3.39 (m, 4H), 1.94 (br, 3H), 1.78 (m, 1H), 0.81 (m, 4H);
ESI-MS: calcd for (C.sub.26H.sub.28N.sub.10OS) 528. found 529
(MH+). HPLC: retention time: 16.27 min. purity: 95%.
Example 13
##STR00117##
[0294] To a solution of compound 3 (163 mg, 0.90 mmol) in THF (10
mL) was added a solution of 3-amino-5-methylpyrazole (87 mg, 0.90
mmol) and DIPEA (0.16 mL, 0.90 mmol) in THF (5 mL) dropwise at
0.degree. C. After addition, the mixture was stirred at 0.degree.
C. for additional 60 minutes. TLC was checked and the starting
materials were consumed. A solution of 1-(4-pyridyl)piperazine (170
mg, 1.03 mmol) and DIPEA (0.26 mL, 1.50 mmol) in THF (5 mL) was
added to the above reaction flak at room temperature. The mixture
was stirred at 70.degree. C. for 2 hours. After cooling to room
temperature, saturated NaHCO.sub.3 in water was added to the flask
and the mixture was extracted by ethyl acetate (3.times.). The
combined organic was washed by brine, dried over sodium sulfate and
concentrated. The resulting crude product was purified by flash
column chromatography on silica gel using DCM/MeOH (7N NH.sub.3):
100/5 v/v as eluent to provide compound 13 as white solids (25 mg,
8%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.80 (br, 1H), 9.50 (br,
1H), 8.16 (d, J=6.4 Hz, 2H), 6.83 (d, J=6.4 Hz, 2H), 6.30 (br, 1H),
3.85 (br, 4H), 3.40 (br, 4H), 2.51 (overlapped by solvent peak,
2H), 2.15 (s, 3H), 1.18 (t, J=7.6 Hz, 3H), ESI-MS: calcd for
(C.sub.18H.sub.23N.sub.9) 365. found 366 (MH+). HPLC: retention
time: 3.43 min. purity: 79%.
Example 14
##STR00118##
[0296] A solution of phenylmagnesium bromide in ether (3M, 16 ml,
48 mmole) was added dropwise to a stirred solution of cyanuric
chloride (5.93 g, 32.16 mmole) in anhydrous dichloromethane at
5.degree. C. After the addition was complete, the reaction mixture
was stirred at 10-20.degree. C. for 3 h. The mixture was cooled to
0.degree. C. and added water dropwise at a rate such that the
temperature of the reaction stayed below 10.degree. C. After
warming to room temperature, the reaction mixture was diluted with
additional water and methylene chloride and passed through a pad of
cilite, washed by saturated ammonium chloride, dried and
concentrated to give 2,4-dichloro-6-phenyl-1,3,5-triazine (14) as
yellow liquid, which solidified after storied in the refrigerator
(1.8 g, 25%). 1H NMR (500 MHz, CDCl.sub.3) .delta. 8.50 (d, J=8.0
Hz, 2H), 7.70 (t, J=8.0 Hz, 1H), 7.55 (t, J=8.0 Hz. 2H).
Example 15
##STR00119##
[0298] THF was added to a mixture of 2-amonoimidazole monosulfate
(85 mg, 0.32 mmole) and sodium hydride (60%, 75 mg, 1.88 mmole) and
the mixture was stirred for 2 hours. Compound 14 (183 mg, 0.81
mmole) was added and the mixture was stirred at 65.degree. C. for 3
hours. Dilute NH.sub.4Cl was added to the reaction mixture,
followed by EtOAc. Light brown precipitate fanned, which was
collected by filtration. The solids were washed by water, ethyl
acetate and dried to give compound 15 (100 mg). The compound was
used directly for further reaction without purification.
Example 16
##STR00120##
[0300] To a solution of compound 15 (80 mg, 0.29 mmol) in DMSO (5
mL) was added compound 1 (70 mg, 0.36 mmol) and DIPEA (0.20 mL,
1.15 mmol). The mixture was heated at 130.degree. C. for 7 minutes
using microwave initiator. After cooled to room temperature,
saturated NaHCO.sub.3 in water was added and the mixture was
extracted by DCM/isopropal (90/10) (3.times.). The organic was
dried (sodium sulfate) and concentrated. The crude product was
purified on silica gel column and eluted by 3% MeOH in DCM to
provide compound 16 as white solids (15 mg, 12%). 1H NMR (400 MHz,
DMSO-d6) .delta. 10.45 (s, 1H), 8.36 (d, J=8.0 Hz, 2H), 7.77 (d,
J=8.8 Hz, 2H), 7.60 (m, 5H), 7.35 (d, J=2.0 Hz, 1H), 56.58 (br,
1H), 6.55 (d, J=2.0 Hz, 1H), 1.82 (m, 1H), 0.83 (m, 4H); ESI-MS:
calcd for (C.sub.22H.sub.19N.sub.7OS) 429. found 430 (MH+). HPLC
(two isomers were detected): retention time: 27.56 min, 23%; 31.25
min., 67%.
Example 17
##STR00121##
[0302] To a solution of compound 7 (1.00 g, 2.93 mmol) in THF (20
mL) was added DIPEA (0.45 mL, 2.60 mmol) and
2-amino-5-methyl-thiazole (285 mg, 2.50 mmol). The mixture was
heated at 150.degree. C. for 10 minutes using microwave initiator.
After cooled to room temperature, 5 mL ethyl acetate was added and
the orange solids on the wall of the tube were scratched off. The
mixture was stirred at room temperature for 30 min and the solids
were collected by filtration to give compound 17 (1.09 g, 88%). The
crude product was used directly for the next step reaction without
further purification.
Example 18
##STR00122##
[0304] A solution of compound 7 (2.00 g, 5.86 mmol) in THF (80 mL)
was cooled by using ice-NaCl batch (bath temperature -20.degree.
C.). A solution of DIPEA (1.00 mL, 5.75 mmol) and
2-amino-5-methyl-thiazole (570 mg, 5.00 mmol) was added to the
above solution at -20.degree. C. (batch temperature) dropwise.
After the addition, the temperature was stirred 0.degree. C. for 2
additional hours and then let it warmed to room temperature. The
solids formed during the reaction was filtered off, washed with THF
followed by ethyl acetate and dried to give light yellow solids of
compound 18 (1.75 g, 83%) The crude product was used directly for
the next step reaction without further purification.
Example 19
##STR00123##
[0306] To a suspension of compound 17 (200 mg, 0.48 mmol) in
isopropal (15 mL) was added 1-hydroxyethylpiperazine (130 mg, 1.00
mmol) and DIPEA (0.17 mL, 1.00 mmol) and the mixture was stirred at
60.degree. C. for 5 minute using a micro wave initiator. After
cooling to room temperature, saturated NaHCO.sub.3 in water was
added to the flask and the mixture was extracted by dichloromethane
(3.times.). The combined organic was washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by flash column chromatography on silica gel using
DCM/MeOH (2N NH.sub.3): 100/5 v/v as eluent to provide compound 19
as white solids (50 mg, 20%). 1H NMR (400 MHz, DMSO-d6) .delta.
11.15 (br, 1H), 10.40 (s, 1H), 7.69 (br, 2H), 7.48 (d, J=8.0 Hz,
2H), 7.00 (br, 1H), 4.40 (br, 1H), 3.76 (br, 4H), 3.49 (m, 2H),
2.40-2.00 (m, 9H, 3.times.CH.sub.2+CH.sub.3), 1.78 (m, 1H), 0.78
(d, J=8.0 Hz, 4H); ESI-MS: calcd for
(C.sub.23H.sub.28N.sub.8O.sub.2S.sub.2) 512. found 513 (MH+). HPLC:
retention time: 14.667 min. purity: 98%.
Example 20
##STR00124##
[0308] To a suspension of compound 17 (500 mg, 1.19 mmol) in
DMSO/isopropal (1/1, 15 mL) was added 4-pyridylpiperazine (188 mg,
1.15 mmol) and DIPEA (0.50 mL, 2.87 mmol) and the mixture was
stirred at 60.degree. C. for 10 minute using a micro wave
initiator. After cooling to room temperature, water was added to
the flask and the solids were collected by filtration, washed by
water, ethyl acetate. The yellow solids were suspended in MeOH/DCM
and mixed with silica gel. After removal of the solvents, the
sample was dry-loaded on silica gel column and purified by flash
column chromatography (DCM/MeOH (2N NH.sub.3): 100/5 v/v as eluent
to provide compound 20 as white solids (50 mg, 8%). 1H NMR (400
MHz, DMSO-d6) .delta. 11.39 (br, 1H), 10.39 (s, 1H), 8.14 (d, J=8.0
Hz, 2H), 7.68 (br, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.00 (br, 1H), 6.83
(d, J=8.0 Hz, 2H), 3.90-3.70 (m, 4H), 3.50-3.30 (m, 4H), 2.30 (br,
3H), 1.78 (m, 1H), 0.79 (d, J=8.0 Hz, 4H); ESI-MS: calcd for
(C.sub.26H.sub.27N.sub.9OS.sub.2) 545. found 546 (MH+). HPLC:
retention time: 20.757 min. purity: 90%.
Example 21
##STR00125##
[0310] To a suspension of compound 17 (200 mg, 0.48 mmol) in
isopropal (15 mL) was added morpholine (0.10 mL, 1.15 mmol) and
DIPEA (0.17 mL, 1.00 mmol) and the mixture was stirred at
60.degree. C. for 5 minute using a micro wave initiator. After
cooling to room temperature, saturated NaHCO.sub.3 in water was
added to the flask and the mixture was extracted by dichloromethane
(3.times.). The combined organic was washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by flash column chromatography on silica gel using
DCM/MeOH (2N NH.sub.3): 100/2 v/v as eluent to provide compound 21
as white solids (50 mg, 22%). 1H NMR (400 MHz, DMSO-d6) .delta.
11.15 (br, 1H), 10.36 (s, 1H), 7.69 (br, 2H), 7.48 (d, J=8.0 Hz,
2H), 7.00 (br, 1H), 4.00-3.50 (m 8H), 2.14 (m, 3H), 1.78 (m, 1H),
0.78 (br, 4H); ESI-MS: calcd for
(C.sub.21H.sub.23N.sub.7O.sub.2S.sub.2) 469. found 470 (MH+). HPLC:
retention time: 29.216 min. purity: 95%.
Example 22
##STR00126##
[0312] To a suspension of compound 17 (100 mg, 0.23 mmol) in
isopropal (5 mL) was added ethanolamine (0.05 mL, 0.82 mmol) and
DIPEA (0.10 mL, 0.50 mmol) and the mixture was stirred at
60.degree. C. for 5 minute using a micro wave initiator. After
cooling to room temperature, saturated NaHCO.sub.3 in water was
added to the flask and the mixture was extracted by dichloromethane
(3.times.). The combined organic was washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by flash column chromatography on silica gel using
DCM/MeOH (2N NH.sub.3): 100/5 v/v as eluent to provide compound 22
as white solids (21 mg, 21%). ESI-MS: calcd for
(C.sub.19H.sub.21N.sub.7O.sub.2S.sub.2) 443. found 444 (MH+).
Example 23
##STR00127##
[0314] To a solution of Potassium ethoxide (24 wt % in ethanol, 100
mL, 253 mmol) was added dry Et.sub.2O (50 mL) under Argon. The
mixture was cooled to 0.degree. C. in ice, diethyl oxalate (18.26
g, 125 mmol), dissolved in Et.sub.2O (17 mL), was added dropwise,
and the reaction mixture was stirred for 30 min. A solution of
CH.sub.3CN (5.18 g (6.57 mL), 125 mmol) in Et.sub.2O (10 mL) was
added, and the mixture was allowed to warm to room temperature and
stirred for 1.5 h. The precipitated solid was collected by
filtration to give compound 23 (17 g, 76% yield). The product was
used without further purification.
Example 24
##STR00128##
[0316] To a suspension of the potassium cyano pyruvate compound 23
(5.00 g, 25.35 mmol) in chloroform (250 mL) was added HCl (2M in
ethyl ester, 20 mL, 40 mmol). Methyl hydrazino formate (2.28 g,
25.35 mmol) was added, the mixture was stirred for 24 h at room
temperature, any precipitated solid was removed by filtration
through a pad of celite, and the filtrate was concentrated to give
an oil. The crude product was purified by column chromatography
(30% ethyl acetate in hexane) to yield 24 (1.33 g, 25%) as a
light-yellow oil; 1H NMR (400 MHz, CDCl.sub.3) .delta.[ppm] 11.94
(br s, 1H, NH), 4.40 (q, 3J=7.1 Hz, 2H), 3.89 (s, 3H), 3.60 (s,
2H), 1.40 (t, 3H, 3J=7.1 Hz); ESI-MS: calcd for
(C.sub.8H.sub.11N.sub.3O.sub.4) 213. found 236 (MNa+).
Example 25
##STR00129##
[0318] To a solution of 24 (1.15 g, 5.39 mmol) in CH.sub.3CN (50
mL) was added triethylamine (1.5 mL, 10.71 mmol) and the mixture
was stirred for 30 min at room temperature. The solvent was removed
in vacuo and the solid residue was recrystallized from ethyl
acetate to give N-methoxycarbonyl-3-aminopyrazole-5-carboxylic acid
ethyl ester (compound 25) (613 mg, 53%) as colorless crystals. 1H
NMR (400 MHz, CDCl.sub.3) S[ppm] 5.90 (s, 1H), 5.42 (br s, 2H),
4.39 (q, 3J=7.1 Hz, 2H), 4.05 (s, 3H), 1.38 (t, 3J=7.1 Hz, 3 H);
ESI-MS: calcd for (C.sub.8H.sub.11N.sub.3O.sub.4) 213. found 236
(MNa+).
Example 26
##STR00130##
[0320] A mixture of compound 3 (420 mg, 2.36 mmol), compound 25
(320 mg, 1.50 mmol) and DIPEA (0.31 mL, 1.80 mmol) in THF/DCM (12
mL/3 mL) was heated at 180.degree. C. for 20 minutes with microwave
initiator. After cooling to room temperature, the mixture was mixed
with silica gel and the solvents were removed in vacuo. The solids
were dry-loaded on a silica gel column and purified by column
chromatography (50% ethyl acetate in hexane) to give compound 26 as
white solids (150 mg, 34%). 1H NMR (400 MHz, CDCl.sub.3) .delta.:
13.68 (br, 1H), 11.17 (br, 1H), 7.16 (br, 1H), 4.31 (q, J=7.1 Hz,
2H), 2.62 (br, 2H), 1.28 (t, J=7.1 Hz, 3H), 1.21 (br, 3H); ESI-MS:
calcd for (C.sub.11H.sub.13ClN.sub.6O.sub.2) 296. found 297
(MH+).
Example 27
##STR00131##
[0322] To a solution of compound 26 (120 mg, 0.40 mmol) in DMSO (5
mL) was added 1-methylpiperazine (0.22 ml, 1.98 mmol) and DIPEA
(0.17 mL, 1.00 mmol) and the mixture was stirred at 60.degree. C.
for 10 minutes with micro wave initiator. After cooling to room
temperature, water was added and yellow solids formed, which was
collected by filtration. The resulting crude product was purified
by flash column chromatography on silica gel using DCM/MeOH (2N
NH.sub.3): 100/3 v/v as eluent to provide compound 27 as
light-yellow solids (115 mg, 80%). 1H NMR (400 MHz, DMSO-d6)
.delta. 13.40 (br, 1H), 9.90 (br, 1H), 7.06 (br, 1H), 4.26 (q,
J=8.0 Hz, 2H), 3.73 (br, 4H), 2.35 (br, 4H), 2.21 (br, 3H), 1.26
(t, J=8.0 Hz, 3H), 1.15 (t, J=8.0 Hz, 3H); ESI-MS: calcd for
(C.sub.16H.sub.24N.sub.8O.sub.2) 360. found 361 (MH+). HPLC:
retention time: 5.195 min. purity: 98%.
Example 28
##STR00132##
[0324] To a solution of compound 27 (90 mg, 0.25 mmol) in
dichloromethane (15 mL) was added diisobutylaluminum hydride (1.-M
solution in THF, 2.00 ml, 2.00 mmol) at 0.degree. C. dropwise and
the mixture was stirred at room temperature for 72 hours, upon
which, the starting material was almost consumed. Rachelle salt (aq
solution, 20 mL) was added and the mixture was stirred at room
temperature for additional 3 hours. The mixture was extracted with
DCM (3.times.) and the combined organic was washed by brine, dried
with sodium sulfate and concentrated. The resulting crude product
was purified by flash column chromatography on silica gel using
DCM/MeOH: 100/20 v/v as eluent to provide compound 28 as colorless
semi-solids (28 mg, 35%). 1H NMR (400 MHz, DMSO-d6) .delta. 12.00
(br, 1H), 9.52 (br, 1H), 6.356 (br, 1H), 5.13 (br, 1H), 4.39 (s,
1H), 3.71 (br, 4H), 3.28 (br, 4H), 2.42 (q, J=7.2 Hz, 2H), 32.17
(s, 1H), 1.16 (t, J=7.2 Hz, 3H); ESI-MS: calcd for
(C.sub.14H.sub.22N.sub.8O) 318. found 319 (MH+). HPLC: retention
time: 1.835 min. purity: 99%.
Example 29
##STR00133##
[0326] A mixture of compound 7 (210 mg, 0.62 mmol), compound 25 (88
mg, 0.41 mmol) and DIPEA (0.08 mL, 0.46 mmol) in THF/(15 mL) was
heated at 180.degree. C. for 40 minutes with micro wave initiator.
After cooling to room temperature, the mixture was mixed with
silica gel and the solvents were removed in vacuo. The solids were
dry-loaded on a silica gel column and purified by pass a pad of
silica gel (5% methanol in DCM) to give compound 29 which was used
for the next step reaction without further purification.
Example 30
##STR00134##
[0328] To a solution of compound 29 (obtained as described above))
in DMSO (10 mL) was added 1-methylpiperazine (0.15 ml, 1.35 mmol)
and DIPEA (0.15 mL, 0.88 mmol) and the mixture was stirred at
60.degree. C. for 10 minutes with micro wave initiator. After
cooling to room temperature, water was added and yellow solids
formed, which was collected by filtration. The resulting crude
product was purified by flash column chromatography on silica gel
using DCM/MeOH (7N NH.sub.3): 100/2 v/v as eluent to provide
compound 30 as light-yellow solids (45 mg, 21% for 2 steps). 1H NMR
(400 MHz, DMSO-d6) .delta. 13.40 (br, 1H), 10.32 (s, 1H), 9.90 (br,
1H), 7.63 (d, J=8.4 Hz, 2H), 7.44 (d, d, J=8.4 Hz, 2H), 6.78 (br,
1H), 4.25 (q, J=7.2 Hz, 2H), 3.60 (br, 4H), 2.35 (br, 4H), 2.17 (s,
3H), 1.77 (m, 1H), 1.25 (t, J=7.2 Hz, 3H), 0.79 (m, 4H); ESI-MS:
calcd for (C.sub.24H.sub.29N.sub.9O.sub.3S) 523. found 524 (MH+).
HPLC: retention time: 19.595 min. purity: 94%.
Example 31
##STR00135##
[0330] A mixture of 2-amino-5-methylthiazol (660 mg, 5.78 mmol) and
benzyl bromide (0.76 mL, 6.36 mmol) in acetone (10 mL) was refluxed
for 5 hours. After cooling to room temperature, the white solids
formed during the reaction was collected by filtration, washed with
acetone and dried under vac. To give compound 31 (350 mg, 22%). 1H
NMR (400 MHz, DMSO-d6) .delta. 9.56 (s, 2H), 7.36-7.16 (m, 5H),
5.17 (s, 1H), 2.15 (s, 3H); ESI-MS: calcd for (free base)
(C.sub.11H.sub.12N.sub.2S) 204. found 205 (MH+).
Example 32
##STR00136##
[0332] A mixture of compound 31 (25 mg, 0.088 mmol), compound 5 (21
mg, 0.11 mmol) and DIPEA (0.02 mL, 0.11 mmol) in THF (1 mL) was
heated at 120.degree. C. for 5 minutes with micro wave initiator.
After cooling to room temperature, 1-methylpiperazine (0.1 mL, 1.00
mmol) and DIPEA (0.2 mL, 0.11 mmol) was added to the mixture and
heated at 60.degree. C. for 5 minutes with micro wave initiator.
Saturated sodium bicarbonate in water was added and the mixture was
extracted with dichloromethane (3.times.). the combined organic was
dried over sodium sulfate and concentrated to give compound 32. The
resulting crude product was not further purified (25 mg, 80%). 1H
NMR (400 MHz, DMSO-d6) .delta. 7.33-7.26 (m, 5H), 6.41 (s, 1H),
5.37 (s, 2H), 3.95 (m, 4H), 2.45 (m, 4H), 2.35 (s, 3H), 2.19 (s,
3H), 2.05 (m, 1H), 1.22 (m, 2H), 0.95 (m, 2H); ESI-MS: calcd for
(C.sub.22H.sub.27N.sub.7S) 421. found 422 (MH+).
Example 33
##STR00137##
[0334] To a suspension of compound 18 (265 mg, 0.63 mmol) in
DMSO/isopropal (15 mL/5 mL) was added morpholine (0.15 mL, 1.72
mmol) and DIPEA (0.15 mL, 0.86 mmol) and the mixture was stirred at
60.degree. C. for 10 minute using a micro wave initiator. After
cooling to room temperature, Water was added to the flask and the
precipitate formed, which was collected by filtration, washed by
water. The crude product was crystallized from methanol/DCM to give
compound 33 as white solids (80 mg, 27%). 1H NMR (400 MHz, DMSO-d6)
.delta. 10.39 (s, 1H), 8.93 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.46
(d, J=8.0 Hz, 2H), 7.17 (s, 1H), 3.70-3.50 (m 8H), 1.99 (s, 3H),
1.77 (m, 1H), 0.79 (br, 4H); ESI-MS: calcd for
(C.sub.21H.sub.23N.sub.7O.sub.2S.sub.2) 469. found 470 (MH+). HPLC:
retention time: 23.125 min. purity: 99%.
Example 34
##STR00138##
[0336] A mixture of 2-amino-5-methylthiazol (1.00 g, 8.76 mmol) and
4-methoxybenzyl bromide (1.53 mL, 10.51 mmol) in acetone (10 mL)
was refluxed for 5 overnight. After cooling to room temperature,
ethyl acetate (.about.5 mL) was added and pink precipitate formed,
which was collected by filtration, washed with acetone/ethyl
acetate and dried under vac. To give compound 34 (250 mg, 11%). 1H
NMR (400 MHz, DMSO-d6) .delta. 9.51 (s, 2H), 7.28 (d, J=8.86, 2H),
7.13 (s, 1H), 6.93 (d, J=8.86, 2H), 5.08 (s, 1H), 3.72 (s, 3H),
2.17 (s, 3H); ESI-MS: calcd for (free base)
(C.sub.12H.sub.15BrN.sub.2OS) 234. found 235 (MH+).
Example 35
##STR00139##
[0338] To a solution of compound 7 (170 mg, 0.50 mmol) in THF (5
mL) was added compound 34 (125 mg, 0.39 mmol) and DIPEA (0.10 mL,
0.53 mmol). After addition, the mixture was heated at 150.degree.
C. for 10 minutes using micro wave initiator. After cooling to room
temperature, 1-methylpiperazine (0.10 ml, 0.90 mmol) and DIPEA
(0.20 mL, 1.06 mmol) was added to the above reaction tube. The
mixture was stirred at 60.degree. C. for 10 minutes using micro
wave initiator. After cooling to room temperature, saturated
NaHCO.sub.3 in water was added and the mixture was extracted by DCM
(3.times.). The combined organic was washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by flash column chromatography on silica gel using
DCM/MeOH (2N NH.sub.3): 100/2 v/v as eluent to provide compound 35
as white solids (160 mg, 76%). 1H NMR (400 MHz, DMSO-d6) .delta.
10.36 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.17
(d, J=8.8 Hz, 2H), 6.99 (s, 1H), 6.85 (d, J=8.8 Hz, 2H), 5.11 (s,
2H), 3.67 (s, 1H), 3.65 (br, 4H), 2.25 (br, 4H), 2.18 (s, 3H), 1.99
(s, 3H), 1.78 (m, 1H), 0.78 (m, 4H); ESI-MS: calcd for
(C.sub.30H.sub.34N.sub.8O.sub.2S.sub.2) 602. found 603 (MH+).
Example 36
##STR00140##
[0340] To a solution of compound 35 (.about.150 mg, 0.25 mmol) in
TFA (10 mL) was heated at 100.degree. C. for 45 minutes using micro
wave initiator. After cooling to room temperature, the solvent was
removed under reduced pressure. Saturated NaHCO.sub.3 was added and
the mixture was extracted by DCM/isopropal (3.times.). The combined
organic was dried over sodium sulfate and concentrated. The
resulting crude product was purified by flash column chromatography
on silica gel using DCM/MeOH (2N NH.sub.3): 100/5 v/v as eluent to
provide compound 36 as white solids (70 mg, 58%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.15 (br, 1H), 10.40 (s, 1H), 7.69 (d, J=8.8 Hz,
2H), 7.50 (m, 2H), 7.00 (br, 1H), 3.76 (m, 4H), 2.33 (m, 4H),
2.18-2.00 (multiple s, 6H), 1.78 (m, 1H), 0.81 (m, 4H); ESI-MS:
calcd for (C.sub.22H.sub.26N.sub.8OS.sub.2) 482. found 483 (MH+).
HPLC: retention time: 16.26 min. purity: 98%.
Example 37
##STR00141##
[0342] To a suspension of compound 19 (400 mg, 0.78 mmol) in
imeOH/DCM (65 mL/15 mL) was added a solution of HCl in ethyl ether
(1 M, 1.00 mL, 1.00 mmol) dropwise and the mixture was stirred at
room temperature for 3 hours. The solvents were removed under
reduced pressure, coevaperated with acetonitrile (3.times.) and
further dried on vacuum line (<50 mmtor) to provide compound 37
as white solids (405 mg, 95%). ESI-MS: calcd for (free base)
(C.sub.23H.sub.28N.sub.8O.sub.2S.sub.2) 512. found 513 (MH+). HPLC:
retention time: 21.899 min. purity: 98%.
Example 38
##STR00142##
[0344] To a suspension of compound 17 (200 mg, 0.49 mmol) in DMSO
(5 mL) was added 3-morpholinopropan-1-amine (0.20 mL, 1.37 mmol)
and DIPEA (0.17 mL, 0.97 mmol) and the mixture was stirred at
60.degree. C. for 15 minute using a micro wave initiator. After
cooling to room temperature, water (.about.15 mL) was added and the
mixture was cooled to 4.degree. C. overnight, during which, yellow
solids of the crude product formed. The solids were collected by
filtration, washed by water, hexanes and then suspended in MeOH/DCM
and mixed with silica gel. After removal of the solvents, the
sample was dry-loaded on silica gel column and purified by flash
column chromatography (DCM/MeOH/: 90/10/v/v/ as eluent to provide
compound 38 as white solids (80 mg, 31%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.15 (br, 1H), 10.40 (s, 1H), 7.69-7.20 (m, 4H), 7.00 (br,
1H), 3.60-3.20 (m, 6H), 2.40-2.00 (m, 9H,
3.times.CH.sub.2+CH.sub.3), 1.80-1.20 (m, 3H), 0.78 (d, J=8.0 Hz,
4H); ESI-MS: calcd for (C.sub.24H.sub.30N.sub.8O.sub.2S.sub.2) 526.
found 527 (MH+). HPLC: retention time: 16.011 min. purity: 95%.
Example 39
##STR00143##
[0346] To a suspension of compound 17 (200 mg, 0.49 mmol) in DMSO
(5 mL) was added N',N'-dimethylethane-1,2-diamine (0.20 mL, 2.27
mmol) and DIPEA (0.17 mL, 0.97 mmol) and the mixture was stirred at
60.degree. C. for 15 minute using a micro wave initiator. After
cooling to room temperature, water (.about.15 mL) was added and the
mixture was cooled to 4.degree. C. overnight, during which, yellow
solids of the crude product formed. The solids were collected by
filtration, washed by water, hexanes and then suspended in MeOH/DCM
and mixed with silica gel. After removal of the solvents, the
sample was dry-loaded on silica gel column and purified by flash
column chromatography (DCM/MeOH/TEA: 90/10/1 v/v/v as eluent to
provide compound 39 as white solids (66 mg, 29%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.15 (br, 1H), 10.52 (s, 1H), 7.69-7.20 (m, 4H),
7.00 (br, 1H), 3.28 (s, 6H), 2.80 (m, 4H), 2.20 (b, 3H), 1.80 (m,
1H), 0.78 (d, J=8.0 Hz, 4H); ESI-MS: calcd for
(C.sub.21H.sub.26N.sub.8OS.sub.2) 470. found 471 (MH+). HPLC:
retention time: 15.040 min. purity: 84%.
Example 40
##STR00144##
[0348] To a suspension of compound 17 (200 mg, 0.49 mmol) in DMSO
(5 mL) was added N1,N1,N2-trimethylethane-1,2-diamine (0.20 mL,
1.55 mmol) and DIPEA (0.17 mL, 0.97 mmol) and the mixture was
stirred at 60.degree. C. for 15 minute using a micro wave
initiator. After cooling to room temperature, water (.about.15 mL)
was added and the mixture was cooled to 4.degree. C. overnight,
during which, yellow solids of the crude product formed. The solids
were collected by filtration, washed by water, hexanes and then
suspended in MeOH/DCM and mixed with silica gel. After removal of
the solvents, the sample was dry-loaded on silica gel column and
purified by flash column chromatography (DCM/MeOH/TEA: 90/10/1
v/v/v as eluent to provide compound 40 as white solids (110 mg,
46%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.25 (br, 1H), 10.34 (br,
1H), 7.69-7.30 (m, 4H), 7.00 (br, 1H), 3.80-1.99 (m, 16H), 1.80 (m,
1H), 0.78 (d, J=8.0 Hz, 4H); ESI-MS: calcd for
(C.sub.22H.sub.28N.sub.8OS.sub.2) 484. found 485 (MH+). HPLC:
retention time: 18.283 min. purity: 100%.
Example 41
##STR00145##
[0350] To a suspension of compound 17 (200 mg, 0.49 mmol) in DMSO
(5 mL) was added butan-1-amine (0.20 mL, 2.02 mmol) and DIPEA (0.17
mL, 0.97 mmol) and the mixture was stirred at 60.degree. C. for 15
minute using a micro wave initiator. After cooling to room
temperature, water (.about.15 mL) was added and the mixture was
cooled to 4.degree. C. overnight, during which, yellow solids of
the crude product Ruined. The solids were collected by filtration,
washed by water, hexanes and then suspended in MeOH/DCM and mixed
with silica gel. After removal of the solvents, the sample was
dry-loaded on silica gel column and purified by flash column
chromatography (DCM/MeOH/TEA: 90/10/1 v/v/v as eluent to provide
compound 41 as white solids (11 mg, 5%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.25 (br, 1H), 10.34 (br, 1H), 7.69-7.30 (m, 4H), 7.00
(br, 1H), 3.80-1.20 (m, 13H), 0.78 (d, J=8.0 Hz, 4H); ESI-MS: calcd
for (C.sub.21H.sub.25N.sub.7OS.sub.2) 455. found 456 (MH+). HPLC:
retention time: 32.437 min. purity: 90%.
Example 42
##STR00146##
[0352] To a suspension of compound 17 (200 mg, 0.49 mmol) in DMSO
(5 mL) was added diethylamine (0.20 mL, 1.94 mmol) and DIPEA (0.17
mL, 0.97 mmol) and the mixture was stirred at 60.degree. C. for 15
minute using a micro wave initiator. After cooling to room
temperature, water (.about.15 mL) was added and the mixture was
cooled to 4.degree. C. overnight, during which, yellow solids of
the crude product formed. The solids were collected by filtration,
washed by water, hexanes and then suspended in MeOH/DCM and mixed
with silica gel. After removal of the solvents, the sample was
dry-loaded on silica gel column and purified by flash column
chromatography (DCM/MeOH/TEA: 90/10/1 v/v/v as eluent to provide
compound 42 as white solids (58 mg, 26%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.25 (br, 1H), 10.34 (br, 1H), 7.65 (d, J=8.4 Hz, 2H),
7.47 (d, J=8.4 Hz, 2H), 7.00 (br, 1H), 3.59-3.20 (m, 4H), 2.30 (br,
3H), 1.78 (m, 1H), 1.20 (br, 3H), 1.00 (br, 3H), 0.78 (m, 4H);
ESI-MS: calcd for (C.sub.21H.sub.25N.sub.7OS.sub.2) 455. found 456
(MH+). HPLC: retention time: 35.371 min. purity: 99%.
Example 43
##STR00147##
[0354] To a suspension of compound 17 (200 mg, 0.49 mmol) in DMSO
(5 mL) was added cyclopropanamine (0.20 mL, 3.50 mmol) and DIPEA
(0.17 mL, 0.97 mmol) and the mixture was stirred at 60.degree. C.
for 15 minute using a micro wave initiator. After cooling to room
temperature, water (.about.15 mL) was added and the mixture was
cooled to 4.degree. C. overnight, during which, yellow solids of
the crude product formed. The solids were collected by filtration,
washed by water, hexanes and then suspended in MeOH/DCM and mixed
with silica gel. After removal of the solvents, the sample was
dry-loaded on silica gel column and purified by flash column
chromatography (DCM/MeOH/TEA: 90/10/1 v/v/v as eluent to provide
compound 43 as white solids (15 mg, 7%). ESI-MS: calcd for
(C.sub.20H.sub.21N.sub.7OS.sub.2) 439. found 440 (MH+).
Example 44
##STR00148##
[0356] To a suspension of compound 17 (200 mg, 0.49 mmol) in DMSO
(5 mL) was added diethylamine (0.20 mL, 2.35 mmol) and DIPEA (0.17
mL, 0.97 mmol) and the mixture was stirred at 60.degree. C. for 15
minute using a micro wave initiator. After cooling to room
temperature, water (.about.15 mL) was added and the mixture was
cooled to 4.degree. C. overnight, during which, yellow solids of
the crude product formed. The solids were collected by filtration,
washed by water, hexanes and then suspended in MeOH/DCM and mixed
with silica gel. After removal of the solvents, the sample was
dry-loaded on silica gel column and purified by flash column
chromatography (DCM/MeOH/TEA: 90/10/1 v/v/v as eluent to provide
compound 44 as white solids (32 mg, 14%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.25 (br, 1H), 10.34 (br, 1H), 7.65 (br, 2H), 7.47 (d,
J=8.4 Hz, 2H), 7.00 (br, 1H), 3.80-3.20 (m, 4H), 2.30 (br, 3H),
1.78 (m, 1H), 1.60-1.20 (m, 6H), 0.78 (m, 4H); ESI-MS: calcd for
(C.sub.22H.sub.25N.sub.7OS.sub.2) 467. found 468 (MH+). HPLC:
retention time: 36.683 min. purity: 98%.
Example 45
##STR00149##
[0358] To a solution of compound 5 (230 mg, 1.21 mmol) in THF (15
mL) was added a solution of 3-amino-5-methylpyrazole (118 mg, 1.21
mmol) and DIPEA (0.21 mL, 1.21 mmol) in THF (15 mL) dropwise at
0.degree. C. After addition, the mixture was stirred at 0.degree.
C. for 2 hours. A solution of 4-aminothiophenol (212 mg, 1.69 mmol)
and sodium hydride (110 mg, 4.58 mmol) in DMF (3 mL) was added to
the above reaction flak at room temperature. The mixture was
stirred at room temperature for 5 hours. Saturated NH.sub.4Cl in
water was added to the flask and the mixture was extracted by DCM
(3.times.). The combined organic was dried over sodium sulfate and
concentrated. The resulting crude product was purified by flash
column chromatography on silica gel using Hexanes/EtOAc: 40/60 v/v
as eluent to provide compound 45 as white solids (180 mg, 44%). 1H
NMR (400 MHz, DMSO-d6) .delta. 11.80 (br, 1H), 9.98 (s, 1H), 7.14
(d, J=8.4 Hz, 2H), 6.60 (d, J=8.4 Hz, 2H), 5.50 (br, 2H), 5.46 (s,
1H), 2.05 (br, 3H), 1.80 (m, 2H), 0.94 (m, 4H); ESI-MS: calcd for
(C.sub.16H.sub.17N.sub.7S) 339. found 340 (MH+). HPLC: retention
time: 20.533 min. purity: 99%.
Example 46
##STR00150##
[0360] A solution of 2-amino-5-methylthiazol (1.30 g, 13.56 mmol)
and DIPEA (2.00 mL, 11.48 mmol) in THF (55 ml) was added dropwise
to a stirred solution of cyanuric chloride (2.50 g, 13.56 mmol) in
THF (70 mL) at -5.degree. C. After the addition was complete, the
reaction mixture was stirred at -5.degree. C. for 15 more minute.
During the stirring, large amount of yellow precipitate formed,
which was collected by filtration, washed with THF (3.times.20 mL),
ethyl acetate (3.times.20 mL) and hexanes (1.times.10 mL). The
compound 46 (2.72 g, 91%) was used directly for further reaction
without purification.
Example 47
##STR00151##
[0362] To a solution of compound 46 (50 mg, 0.19 mmol) in DMF (5
mL) was added 1-methylpiperazine (0.10 mL, 0.90 mmol) and the
mixture was stirred at room temperature for 1 hours then at
60.degree. C. for 10 minutes using microwave initiator. After
cooling to room temperature, water was added and the solids were
collected by filtration, washed with water, then hexanes to provide
compound 47 as white solids (20 mg, 27%). 1H NMR (400 MHz, DMSO-d6)
.delta. 10.89 (s, 1H), 7.00 (s, 1H), 3.78 (br, 8H), 2.35 (m, 11H),
2.18 (s, 6H); ESI-MS: calcd for (C.sub.17H.sub.27N.sub.9S) 389.
found 390 (MH+). HPLC: retention time: 1.813 min. purity: 93%.
Example 48
##STR00152##
[0364] To a solution of compound 46 (565 mg, 2.16 mmol) in DMF (60
mL) was added a solution of 1-methylpiperazine (0.20 mL, 1.80 mmol)
and DIPEA (0.35 mL, 1.80 mmol) in DMF (30 mL) dropwise at
-15.degree. C. After addition, the mixture was stirred at 0.degree.
C. for 30 minutes. A solution of 4-aminothiophenol (700 mg, 5.60
mmol) and sodium hydride (60%, 260 mg, 6.50 mmol) in DMF (7 mL) was
added to the above reaction flak at room temperature. The mixture
was stirred at room temperature for overnight. Saturated NH.sub.4Cl
in water was added to the flask and the mixture was extracted by
DCM/isopropal (v/v: 97/3, 3.times.). The combined organic was
washed with water, dried over sodium sulfate and concentrated. The
resulting crude product was purified by flash column chromatography
on silica gel using methanol/DCM: 10/90 v/v as eluent to provide
compound 48 as white solids (320 mg, 43%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.20 (br, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.00 (br,
1H), 6.60 (d, J=8.4 Hz, 2H), 5.60 (br, 2H), 3.80 (m, 4H), 2.25 (m,
10H); ESI-MS: calcd for (C.sub.18H.sub.22N.sub.8S.sub.2) 414. found
415 (MH+). HPLC: retention time: 11.648 min. purity: 97%.
Example 49
##STR00153##
[0366] To a solution of compound 46 (1.30, 4.96 mmol) in DMF (60
mL) was added a solution of 1-methylpiperazine (0.42 mL, 3.81 mmol)
and DIPEA (0.66 mL, 3.81 mmol) in DMF (50 mL) dropwise at
-15.degree. C. After addition, the mixture was stirred at 0.degree.
C. for 30 minutes. A solution of 3-aminothiophenol (700 mg, 5.60
mmol) and sodium hydride (60%, 260 mg, 6.50 mmol) in DMF (7 mL) was
added to the above reaction flak at room temperature. The mixture
was stirred at room temperature for overnight. Saturated NH.sub.4Cl
in water (20 mL) was added to the flask and the mixture was
concentrated. The residue was washed by water, decanted and
suspended in DCM. The resulting crude product was purified by flash
column chromatography on silica gel using methanol/DCM: 15/85 v/v
as eluent to provide compound 49 as white solids (210 mg, 13%). 1H
NMR (400 MHz, DMSO-d6) .delta. 11.80 (br, 1H), 7.20-6.80 (m, 5H),
5.20 (br, 2H), 3.80 (m, 4H), 3.00 (m, 4H), 2.25 (m, 6H); ESI-MS:
calcd for (C.sub.18H.sub.22N.sub.8S.sub.2) 414. found 415
(MH+).
Example 50
##STR00154##
[0368] To a solution of compound 7 (150 mg, 0.49 mmol) in THF (15
mL) was added a solution of 2-amino-5-chlorothiozole (54 mg, 0.40
mmol) and DIPEA (0.09 mL, 0.49 mmol) in 10-20 mL microwave vial.
Vial was sealed with a cap and the mixture was allowed to stir at
150.degree. C. for 5 min. in the microwave synthesizer. Next,
compound 1-methy piperazine (0.07 mL, 0.59 mmol) and DIPEA (0.10
mL, 0.59 mmol) were added to the above mixture and allowed to stir
at 60.degree. C. for 10 min. in the microwave synthesizer.
Saturated NaHCO.sub.3 in water was added and the mixture was
extracted by ethyl acetate (3.times.50 mL). The combined organic
was washed by brine, dried over sodium sulfate and concentrated.
The residue was chromatographed on a silica gel column eluted with
0-5% MeOH/DCM afforded 50 white solid (30 mg, 14%). 1H NMR (400
MHz, DMSO-d6) .delta. 11.70 (bs, 1H, NH), 10.42 (s, 1H, NH),
7.85-7.17 (m, 5H, Ar--H), 3.83-3.51 (m, 4H, 2CH.sub.2), 2.46-2.28
(m, 4H, 2CH.sub.2), 2.20 (s, 3H, CH.sub.3), 1.84-1.78 (m, 1H, CH),
0.81-0.80 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.21H.sub.23ClN.sub.8OS.sub.2) 502. found 503 [M+H]+. HPLC:
retention time: 20.70 min. purity: 91%.
Example 51
##STR00155##
[0370] To a solution of 3-methylbutyl aldehyde (0.9 mL, 7.18 mmol)
in Et.sub.2O (15 mL) was added 5,5-dibromobarbituric acid (1.0 g,
3.59 mmol). Reaction was stirred at room temperature for 18 h.
Mixture was filtered, washed with ether and concentrated. Residue
was washed with hexane, filtered and concentrated. Residue was
dissolved in EtOH (20 mL) and thiourea was added. Mixture was
refluxed for 1 d. Reaction was neutralized with 7N ammonia and
concentrated. Residue was chromatographed on a silica gel column
eluted with 1-10% MeOH/DCM afforded 51. 1H NMR (400 MHz, DMSO-d6)
.delta. 6.72 (d, J=1.2 Hz, H, Ar--H), 4.96 (bs, 2H, NH2), 3.03-2.96
(m, 1H, CH), 1.27 (s, 3H, CH.sub.3), 1.25 (s, 3H, CH.sub.3);
ESI-MS: calcd for (C.sub.6H.sub.10N.sub.2S) 142. found 143
[M+H]+.
Example 52
##STR00156##
[0372] Compound 7 (200 mg, 0.59 mmol) was reacted with compound 51
and treated as described for preparation of compound 50. After
purification, compound 52 was obtained as light yellow solid (50
mg, 17%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.25 (bs, 1H, NH),
10.41 (s, 1H, NH), 7.74-7.72 (m, 2H, Ar--H), 7.52 (d, J=9.3 Hz, 2H,
Ar--H), 6.98 (bs, 1H, Ar--H), 3.86-3.54 (m, 4H, 2CH.sub.2),
2.98-2.80 (m, 1H, CH), 2.42-2.28 (m, 4H, 2CH.sub.2), 2.20 (s, 3H,
CH.sub.3), 1.84-1.78 (m, 1H, CH), 1.15 (bs, 6H, 2CH.sub.3),
0.83-0.81 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.24H.sub.30N.sub.8OS.sub.2) 510. found 511 [M+H]+. HPLC:
retention time: 19.86 min. purity: 95%.
Example 53
##STR00157##
[0374] Compound 7 (300 mg, 0.88 mmol) was reacted syquencely with
5-cyclopropyl-1H-pyrazol-3-amine and 1-methylpiperazine as
described for preparation of compound 50. compound 53 was obtained
as light yellow solid (10 mg, 3%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.66 (bs, 1H, NH), 10.40 (s, 1H, NH), 9.49 (bs, 1H, NH),
7.78-7.68 (m, 2H, Ar--H), 7.45 (d, J=8.4 Hz, 2H, Ar--H), 5.33 (bs,
1H, Ar--H), 3.65-3.56 (m, 4H, 2CH.sub.2), 3.10-3.08 (m, 1H, CH),
2.39-2.31 (m, 4H, 2CH.sub.2), 2.21 (s, 3H, CH.sub.3), 1.81-1.75 (m,
1H, CH), 1.15 (bs, 6H, 2CH.sub.3), 1.26-1.22 (m, 4H, Ar--H),
0.77-0.76 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.24H.sub.29N.sub.8OS) 491. found 492 [M+H]+. HPLC: retention
time: 15.02 min. purity: 97%.
Example 54
##STR00158##
[0376] To a solution of compound 7 (300 mg, 0.88 mmol) in THF (15
mL) was added a solution of 2-amino-5-tert-butylpyrazole (98 mg,
0.70 mmol) and DIPEA (0.16 mL, 0.88 mmol). The reaction mixture was
let to stir at room temperature for 3 h. Then, 1-methyl piperazine
(0.15 mL, 1.32 mmol) and DIPEA (0.23 mL, 1.32 mmol) was added to
the above reaction flak at room temperature. The mixture was
stirred at room temperature for overnight. Saturated NaHCO.sub.3 in
water was added to the flask and the mixture was extracted by ethyl
acetate (3.times.50 mL). The combined organic was washed by brine,
dried over sodium sulfate and concentrated. The residue was
chromatographed on a silica gel column eluted with 0-5% MeOH/DCM
afforded 54 as off white solid (250 mg, 56%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.88 (s, 1H, NH), 10.37 (s, 1H, NH), 9.59 (s, 1H,
NH), 7.70-7.47 (m, 4H, Ar--H), 5.60 (s, 1H, Ar--H), 3.69-3.67 (m,
2H, CH.sub.2), 2.33-2.31 (m, 2H, CH.sub.2), 2.20 (s, 3H, CH.sub.3),
1.84-1.78 (m, 1H, CH), 1.20 (bs, 10H, CH, 3CH.sub.3), 0.82-0.80 (m,
4H, Ar--H); ESI-MS: calcd for (C.sub.25H.sub.33N.sub.9OS) 507.
found 508 [M+H]+. HPLC: retention time: 17.06 min. purity:
100%.
Example 55
##STR00159##
[0378] Compound 7 (300 mg, 0.88 mmol) was reacted syquencely with
5-cyclobutyl-1H-pyrazol-3-amine and 1-methylpiperazine as described
for preparation of compound 50. compound 55 was obtained as light
yellow solid (140 mg, 31%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.88
(bs, 1H, NH), 10.46 (s, 1H, NH), 9.52 (bs, 1H, NH), 7.77-7.48 (m,
4H, Ar--H), 5.38 (s, 1H, Ar--H), 3.67 (bs, 2H, CH.sub.2), 2.31 (bs,
2H, CH.sub.2), 2.20 (s, 3H, CH.sub.3), 2.12-1.75 (m, 7H, CH,
3CH.sub.2), 1.24-1.16 (m, 1H, CH), 0.84-0.82 (m, 4H, Ar--H);
ESI-MS: calcd for (C.sub.25H.sub.31N.sub.9OS) 505. found 506
[M+H]+. HPLC: retention time: 16.75 min. purity: 100%.
Example 56
##STR00160##
[0380] To a solution of cyanuric chloride (300 mg, 1.63 mmol) in
THF (16 mL) was added 2-amino-5-isopropylpyrazole (263 mg, 1.63
mmol) and DIPEA (0.28 mL, 1.63 mmol) at 0.degree. C. The reaction
mixture was let to stir at 0.degree. C. to room temperature for 2
h. Then, 1-methylpiperazine (0.18 mL, 1.63 mmol) and DIPEA (0.28
mL, 1.90 mmol) were added to the above mixture and allowed to stir
at room temperature for 3 hours. Next, compound (I) (628 mg, 3.25
mmol) and DIPEA (0.57 mL, 2.25 mmol) were added to the mixture and
stirred at room temperature overnight. Saturated NaHCO.sub.3 in
water was added and the mixture was extracted by ethyl acetate
(3.times.50 mL). The combined organic was washed by brine, dried
over sodium sulfate and concentrated. The residue was
chromatographed on a silica gel column eluted with 0-5% MeOH/DCM
afforded 56 as light yellow solid (110 mg, 37%). .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.77 (bs, 1H, NH), 10.42 (s, 1H, NH), 9.50
(bs, 1H, NH), 7.73 (bs, 2H, Ar--H), 7.48 (d, J=8.4 Hz, 2H, Ar--H),
5.40 (bs, 1H, Ar--H), 3.68 (bs, 4H, 2CH.sub.2), 2.33 (bs, 4H,
2CH.sub.2), 2.21 (s, 3H, CH.sub.3), 1.83-1.81 (m, 1H, CH), 1.24
(bs, 3H, CH.sub.3), 1.05 (bs, 3H, CH.sub.3), 0.84-0.82 (m, 4H,
Ar--H); ESI-MS: calcd for (C.sub.24H.sub.31N.sub.9OS) 493. found
494 [M+H]+. HPLC: retention time: 15.38 min. purity: 99%.
Example 57
##STR00161##
[0382] Compound 2 (300 mg, 0.88 mmol) was reacted syquencely with
5-propyl-1H-pyrazol-3-amine and 1-methylpiperazine as described for
preparation of compound 54. compound 57 was obtained obtained as
light yellow solid (35 mg, 8%). 1H NMR (400 MHz, DMSO-d6) .delta.
11.02 (bs, 1H, NH), 10.34 (s, 2H, NH), 7.63 (d, J=8.8 Hz, 2H,
Ar--H), 7.42 (d, J=8.4 Hz, 2H, Ar--H), 5.17 (bs, 1H, Ar--H), 4.32
(bs, 2H, CH.sub.2), 3.44-3.42 (m, 4H, 2CH.sub.2), 2.39-2.35 (m, 2H,
CH.sub.2), 2.21-2.13 (m, 4H, 2CH.sub.2), 2.13 (s, 3H, CH.sub.3),
1.81-1.76 (m, 2H, CH.sub.2), 1.55-1.49 (m, 2H, CH.sub.2), 1.87 (t,
J=7.6 Hz, 3H, CH.sub.3), 0.83-0.80 (m, 4H, Ar--H); ESI-MS: calcd
for (C.sub.24H.sub.31N.sub.9OS) 493. found 494 [M+H]+. HPLC:
retention time: 43.26 min. purity: 98%.
Example 58
##STR00162##
[0384] To a solution of compound 3 (180 mg, 0.95 mmol) in THF (10
mL) was added a solution of 2-amino-5-methylthiozole (110 mg, 0.95
mmol) and DIPEA (0.17 mL, 0.95 mmol) in THF (5 mL) dropwise at
0.degree. C. The reaction mixture was let to stir at 0.degree. C.
to room temperature for 3 h. Then, a solution of compound 1 (280
mg, 1.50 mmol) and DIPEA (0.33 mL, 1.90 mmol) in THF (5 mL) was
added to the above reaction flask at room temperature. The mixture
was stirred at room temperature for overnight. Saturated
NaHCO.sub.3 in water was added to the flask and the mixture was
extracted by ethyl acetate (3.times.50 mL). The combined organic
was washed by brine, dried over sodium sulfate and concentrated.
The residue was chromatographed on a silica gel column eluted with
DCM/MeOH (30:1) afforded 58 as light yellow solid (25 mg, 6%). 1H
NMR (400 MHz, DMSO-d6) .delta. 11.83 (s, 1H, NH), 10.48 (s, 1H,
NH), 7.79-7.76 (m, 2H, Ar--H), 7.56 (d, J=8.5 Hz, 2H, Ar--H), 6.98
(s, 1H, Ar--H), 2.63 (dd, J=15.1 Hz, 2H, CH.sub.2), 2.11 (bs, 3H,
CH.sub.3), 1.81 (m, 1H, CH), 1.21 (t, J=7.5 Hz, 3H, CH.sub.3);
ESI-MS: calcd for (C.sub.19H.sub.20N.sub.6OS.sub.2) 412. found 413
[M+H]+. HPLC: retention time: 26.59 min. purity: 96%.
Example 59
##STR00163##
[0386] Compound 5 (50 mg, 0.26 mmol) was reacted sequencely with
2-amino-5-methylthiozole and compound 1 as described for
preparation of 58. Compound 59 was obtained as white solid (5 mg,
4%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.72 (bs, 1H, NH), 10.45
(s, 1H, NH), 7.74 (bs, 2H, Ar--H), 7.53 (d, J=8.3 Hz, 2H, Ar--H),
6.98 (bs, 1H, Ar--H), 2.11 (bs, 3H, CH.sub.3), 1.90 (m, 1H, CH),
1.81 (m, 1H, CH), 1.06 (d, J=6.4 Hz, 4H, Ar--H), 0.81 (d, J=6.2 Hz,
4H, Ar--H); ESI-MS: calcd for (C.sub.20H.sub.20N.sub.6OS.sub.2)
424. found 425 [M+H]+. HPLC: retention time: 30.64 min. purity:
94%
Example 60
##STR00164##
[0388] Compound 7 (300 mg, 0.88 mmol) was reacted sequencely with
thiazol-2-amine and compound 1 as described for the preparation of
compound 58. Compound 60 was obtained as white solid (80 mg, 19%).
1H NMR (400 MHz, DMSO-d6) .delta. 11.59 (bs, 1H, NH), 10.38 (s, 1H,
NH), 7.67 (d, J=8.8 Hz, 2H, Ar--H), 7.51 (d, J=8.7 Hz, 2H, Ar--H),
7.38 (s, 1H, Ar--H), 7.15 (bs, 1H, Ar--H), 3.84-3.53 (m, 4H,
2CH.sub.2), 2.36-2.25 (m, 4H, 2CH.sub.2), 2.18 (s, 3H, CH.sub.3),
1.82-1.78 (m, 1H, CH), 0.82 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.21H.sub.24N.sub.8OS.sub.2) 468. found 469 [M+H]+. HPLC:
retention time: 15.59 min. purity: 76%.
Example 61
##STR00165##
[0390] Compound 7 (300 mg, 0.88 mmol) was reacted sequencely with
4,5-dimethylthiazol-2-amine and compound 1 as described for the
preparation of compound 58. Compound 61 was obtained as white solid
(47 mg, 11%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.22 (bs, 1H, NH),
10.41 (s, 1H, NH), 7.72-7.69 (m, 2H, Ar--H), 7.50 (d, J=8.4 Hz, 2H,
Ar--H), 3.79-3.55 (m, 4H, 2CH.sub.2), 2.34-2.25 (m, 4H, 2CH.sub.2),
2.18 (s, 3H, CH.sub.3), 2.07 (s, 6H, 2CH.sub.3), 1.82-1.79 (m, 1H,
CH), 0.81 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.23H.sub.28N.sub.8OS.sub.2) 496. found 497 [M+H]+. HPLC:
retention time: 17.23 min. purity: 97%.
Example 62
##STR00166##
[0392] A solution of 3-hydroxybenzalinidine (2.00 g, 9.38 mmol) and
DIPEA (1.70 mL, 9.38 mmol) in THF (15 mL) was added dropwise to a
stirred solution of (1.73 g, 9.38 mmol) in THF (30 mL) at
-10.degree. C. Reaction mixture was let to stir for 1 h at this
temperature. Saturated ammonium chloride was added to the reaction
mixture and the mixture was extracted with ethyl acetate
(1.times.100 mL). The organic layer was washed by brine, dried
(Na.sub.2SO.sub.4) and concentrated to give compound 62 as white
solid (2.60 g, 77% yield).
Example 63
##STR00167##
[0394] Compound 62 (300 mg, 0.83 mmol) was reacted sequencely with
2-amino-5-methylthiozole and 1-methylpiperazine as described for
preparation of compound 58. Compound 63 was obtained as white solid
(33 mg, 8%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.45 (bs, 1H, NH),
10.20 (s, 1H, NH), 7.88-7.72 (m, 4H, Ar--H), 7.57 (t, J=8.0 Hz, 1H,
Ar--H), 7.47-7.44 (m, 1H, Ar--H), 7.33 (t, J=8.4 Hz, 2H, Ar--H),
7.08 (t, J=7.2 Hz, 1H, Ar--H), 7.00 (bs, 1H, Ar--H), 3.88-3.63 (m,
4H, 2CH.sub.2), 2.40-2.30 (m, 4H, 2CH.sub.2), 2.17 (s, 3H,
CH.sub.3); ESI-MS: calcd for (C.sub.25H.sub.26N.sub.8O.sub.2S) 502.
found 503 [M+H]+. HPLC: retention time: 18.96 min. purity: 90%.
Example 64
##STR00168##
[0396] Compound 7 (300 mg, 0.88 mmol) was reacted sequencely with
4-methylthiazol-2-amine and 1-methylpiperazine as described for
preparation of 58. Compound 64 was obtained as white solid (60 mg,
14%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.49 (bs, 1H, NH), 10.37
(s, 1H, NH), 7.66 (d, J=8.8 Hz, 2H, Ar--H), 7.50 (d, J=8.8 Hz, 2H,
Ar--H), 6.68 (bs, 1H, Ar--H), 3.80 (bs, 2H, CH.sub.2), 3.50 (bs,
2H, CH.sub.2), 2.34 (bs, 2H, CH.sub.2), 2.25-2.21 (m, 5H, CH.sub.2,
CH.sub.3), 2.17 (s, 3H, CH.sub.3), 1.83-1.77 (m, 1H, CH), 0.82 (m,
4H, Ar--H); ESI-MS: calcd for (C.sub.22H.sub.26N.sub.8OS.sub.2)
482. found 483 [M+H]+. HPLC: retention time: 16.72 min. purity:
97%.
Example 65
##STR00169##
[0398] To a solution of 4-aminothiophenol (1.00 g, 7.99 mmol) and
pyridine (0.97 mL, 11.99 mmol) in THF (30 mL) at 0.degree. C. was
added a solution of isobytric anhydride (1.33 mL, 7.99 mmol) in THF
(40 mL) dropwise. The reaction was stirred from 0.degree. C. to
room temperature for overnight, diluted with EtOAc (100 mL), washed
with 1 N HCl (100 mL.times.5), dried over Na.sub.2SO.sub.4,
concentrated, and dried under vacuum to yield the compound 65 as a
yellow solid, which was used for further reaction without
purification.
Example 66
##STR00170##
[0400] Cyanuric chloride (300 mg, 1.63 mmol) was reacted
sequentially with 2-amino-5-methylthiozole, compound 65 and
1-methylpiperazine as described for preparation of 2. compound 66
was obtained as white solid (60 mg, 8%). 1H NMR (400 MHz, DMSO-d6)
.delta. 10.05 (s, 1H, NH), 9.00 (s, 1H, NH), 7.74-7.72 (m, 2H,
Ar--H), 7.51-7.49 (m, 2H, Ar--H), 7.18 (s, 1H, Ar--H), 3.73-3.67
(m, 4H, 2CH.sub.2), 2.67-2.59 (m, 1H, CH), 2.37-2.28 (m, 4H,
2CH.sub.2), 2.20 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3), 1.12
(s, 3H, CH.sub.3), 1.11 (s, 3H, CH.sub.3); ESI-MS: calcd for
(C.sub.22H.sub.28N.sub.8OS.sub.2) 484. found 485 [M+H]+. HPLC:
retention time: 7.42 min. purity: 94%.
Example 67
##STR00171##
[0402] Cyanuric chloride (300 mg, 1.63 mmol) was reacted
sequentially with 2-amino-5-methylthiozole,
N-(4-mercaptophenyl)acetamide and 1-methylpiperazine as described
for preparation of 2. Compound 67 was obtained as white solid (63
mg, 10%). 1H NMR (400 MHz, DMSO-d6) .delta. 10.17 (s, 1H, NH), 8.97
(s, 1H, NH), 7.71-7.68 (m, 2H, Ar--H), 7.51-7.49 (m, 2H, Ar--H),
7.18 (s, 1H, Ar--H), 3.72-3.66 (m, 4H, 2 CH.sub.2), 2.67-2.59 (m,
1H, CH), 2.35-2.32 (m, 4H, 2CH.sub.2), 2.20 (s, 3H, CH.sub.3), 2.08
(s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3); ESI-MS: calcd for
(C.sub.20H.sub.22N.sub.8OS.sub.2) 456. found 457 [M+H]+. HPLC:
retention time: 4.12 min. purity: 80%.
Example 68
##STR00172##
[0404] A solution of iso-butylmagnesium bromide in ether (2M, 35
ml, 70.0 mmole) was added dropwise to a stirred solution of
cyanuric chloride (5.28 g, 28.63 mmole) in anhydrous
dichloromethane at -5.degree. C. After the reaction was completed
as indicated by TLC, water was added water dropwise at a rate such
that the temperature of the reaction stayed below 10.degree. C.
After warming to room temperature, the reaction mixture was diluted
with additional water and methylene chloride and passed through a
pad of cilite, washed by saturated ammonium chloride, dried and
concentrated to give 2,4-dichloro-6-iso-butyl-1,3,5-triazine as
yellow slurry liquid residue. The crude product was passed through
a pad of silica gel eluted with 10% ethyl acetate in hexanes to
give 68 as the light yellow liquid (3.0 g, 51%). 1H NMR (500 MHz,
CDCl.sub.3) .delta. 2.75 (d, J=7.0 Hz, 2H), 2.29 (m, 1H), 0.97 (d,
J=7.0 Hz. 6H).
Example 69
##STR00173##
[0406] Compound 68 (300 mg, 1.63 mmol) was reacted sequentially
with 2-amino-5-methylthiozole and N-(4-mercaptophenyl)acetamide as
described for preparation of 58. Compound 69 was obtained as white
solid (53 mg, 9%). 1H NMR (400 MHz, DMSO-d6) .delta. 10.18 (s, 1H,
NH), 9.03 (s, 1H, NH), 7.72-7.70 (m, 2H, Ar--H), 7.55-7.50 (m, 2H,
Ar--H), 7.10 (s, 1H, Ar--H), 2.54 (d, J=7.2 Hz, 2H, CH.sub.2),
2.16-2.12 (m, 1H, CH), 2.06 (s, 3H, CH.sub.3), 2.02 (s, 3H,
CH.sub.3), 0.91 (s, 3H, CH.sub.3), 0.89 (s, 3H, CH.sub.3); ESI-MS:
calcd for (C.sub.19H.sub.22N.sub.6OS.sub.2) 414. found 415 [M+H]+.
HPLC: retention time: 23.79 min. purity: 99%.
Example 70
##STR00174##
[0408] Compound 7 (500 mg, 1.47 mmol) was reacted sequentially with
2-amino-5-methylthiozole and 1-methylpiperazine as described for
preparation of 58. Compound 70 was obtained as white solid (70 mg,
6%). 1H NMR (400 MHz, DMSO-d6) .delta. 10.42 (s, 1H, NH), 8.96 (s,
1H, NH), 7.72-7.70 (m, 2H, Ar--H), 7.51-7.49 (m, 2H, Ar--H), 7.19
(s, 1H, Ar--H), 3.72-2.66 (m, 4H, 2CH.sub.2), 2.35-2.32 (m, 4H,
2CH.sub.2), 2.20 (s, 3H, CH.sub.3), 2.02 (s, 3H, CH.sub.3),
1.83-1.79 (m, 1H, CH), 0.83-0.81 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.22H.sub.26N.sub.8OS.sub.2) 482. found 483 [M+H]+. HPLC:
retention time: 7.42 min. purity: 99%.
Example 71
##STR00175##
[0410] To a solution of cyanuric chloride (300 mg, 1.63 mmol) in
THF (10 mL) was added dropwise a solution of compound 65 (320 mg,
1.63 mmol) and DIPEA (0.28 mL, 1.63 mmol) in THF (5 mL) at
0.degree. C. The reaction mixture was let to stir in 10-20 mL
microwave vial at 0.degree. C. to room temperature for 2 h. Then,
2-amino-5-methylthiazole (150 mg, 1.30 mmol) and DIPEA (0.25 mL,
1.30 mmol) were added to the mixture and vial was sealed with a
cap. The mixture was allowed to stir at 150.degree. C. for 5 min.
in the microwave synthesizer (Biotage, Initiator 2.0). Next,
1-methylpiperazine (0.18 mL, 1.63 mmol) and DIPEA (0.28 mL, 1.90
mmol) were added to the above mixture and allowed to stir at
60.degree. C. for 10 min. in the microwave synthesizer. Saturated
NaHCO.sub.3 in water was added and the mixture was extracted by
ethyl acetate (3.times.50 mL). The combined organic was washed by
brine, dried over sodium sulfate and concentrated. The residue was
recrystallized with DCM/MeOH mixture to give 71 as white solid (110
mg, 14%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.28 (s, 1H, NH),
10.53 (s, 1H, NH), 7.75-7.73 (m, 2H, Ar--H), 7.51 (d, J=8.8 Hz, 2H,
Ar--H), 6.97 (s, 1H, Ar--H), 3.78-3.61 (m, 4H, CH.sub.2), 2.65-2.58
(m, 1H, CH), 2.35-2.27 (m, 4H, CH.sub.2), 2.19 (s, 6H, CH.sub.3),
1.12 (s, 3H, CH.sub.3), 1.10 (s, 3H, CH.sub.3); ESI-MS: calcd for
(C.sub.22H.sub.28N.sub.8OS.sub.2) 484. found 485 [M+H]+. HPLC:
retention time: 17.69 min. purity: 96%.
Example 72
##STR00176##
[0412] Compound 68 (300 mg, 1.46 mmol) was reacted sequentially
with 2-amino-5-methylthiozole and N-(4-mercaptophenyl)acetamide
using procedure similar to the preparation of 71. Compound 72 was
obtained as white solid (300 mg, 50%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.84 (s, 1H, NH), 10.22 (s, 1H, NH), 7.76-7.74 (m, 2H,
Ar--H), 7.56 (d, J=8.4 Hz, 2H, Ar--H), 6.99 (s, 1H, Ar--H),
2.51-2.47 (m, 3H), 2.21-2.08 (m, 6H), 0.92 (s, 3H, CH.sub.3), 0.91
(s, 3H, CH.sub.3); ESI-MS: calcd for
(C.sub.19H.sub.22N.sub.6OS.sub.2) 414. found 415 [M+H]+. HPLC:
retention time: 26.43 min. purity: 96%.
Example 73
##STR00177##
[0414] Cyanuric chloride (300 mg, 1.63 mmol) was reacted
sequentially with 2-amino-5-methylthiozole,
N-(4-mercaptophenyl)acetamide and 1-methylpiperazine as described
for preparation of 71. Compound 73 was obtained as white solid (270
mg, 36%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.31 (s, 1H, NH),
10.16 (s, 1H, NH), 7.71-7.69 (m, 2H, Ar--H), 7.51 (d, J=8.4 Hz, 2H,
Ar--H), 6.99 (s, 1H, Ar--H), 3.77-3.51 (m, 4H, 2CH.sub.2),
2.51-2.20 (m, 10H, 2CH.sub.2, 2CH.sub.3), 2.07 (s, 3H, CH.sub.3);
ESI-MS: calcd for (C.sub.20H.sub.24N.sub.8OS.sub.2) 456. found 457
[M+H]+. HPLC: retention time: 12.32 min. purity: 96%.
Example 74
##STR00178##
[0416] Compound 7 (200 mg, 0.59 mmol) was reacted sequentially with
2-amino-5-ieopropylthiozole (compound 51) and 1-methylpiperazine
using the procedure similar to the preparation of 71. Compound 74
was obtained as light yellow solid (50 mg, 17%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.25 (bs, 1H, NH), 10.41 (s, 1H, NH), 7.74-7.72
(m, 2H, Ar--H), 7.52 (d, J=9.3 Hz, 2H, Ar--H), 6.98 (bs, 1H,
Ar--H), 3.86-3.54 (m, 4H, 2CH.sub.2), 2.98-2.80 (m, 1H, CH),
2.42-2.28 (m, 4H, 2CH.sub.2), 2.20 (s, 3H, CH.sub.3), 1.84-1.78 (m,
1H, CH), 1.15 (bs, 6H, 2CH.sub.3), 0.83-0.81 (m, 4H, Ar--H);
ESI-MS: calcd for (C.sub.24H.sub.30N.sub.8OS.sub.2) 510. found 511
[M+H]+. HPLC: retention time: 19.86 min. purity: 95%.
Example 75
##STR00179##
[0418] Compound 3 (300 mg, 1.69 mmol) was reacted sequentially with
2-amino-5-methylthiozole and methyl piperazine using procedure
similar to the preparation of 71. Compound 75 was obtained as
yellow solid (140 mg, 26%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.28
(s, 1H, NH), 7.04 (s, 1H, Ar--H), 3.80-3.79 (bs, 4H, 2CH.sub.2),
2.53-2.46 (m, 2H, CH.sub.2), 2.34-2.30 (m, 4H, 2CH.sub.2), 2.18 (s,
3H, CH.sub.3), 1.18 (t, J=7.6 Hz, 1H, CH.sub.3); ESI-MS: calcd for
(C.sub.14H.sub.21N.sub.7S) 319. found 320 [M+H]+. HPLC: retention
time: 2.62 min. purity: 97%.
Example 76
##STR00180##
[0420] Compound 7 (300 mg, 0.88 mmol) was reacted sequentially
sequentially with 3-methylisoxazol-5-amine and 1-methylpiperazine
using procedure similar to the preparation of 71. Compound 76 was
obtained as light yellow solid (20 mg, 5%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.23 (bs, 1H, NH), 10.56 (s, 1H, NH), 7.79-7.51
(m, 4H, Ar--H), 4.61-4.51 (m, 2H, CH.sub.2), 3.44-3.33 (m, 4H,
2CH.sub.2), 3.07-3.01 (m, 2H, CH.sub.2), 2.75 (s, 3H, CH.sub.3),
2.00-1.81 (m, 4H, CH.sub.3, CH), 0.82 (m, 4H, Ar--H); ESI-MS: calcd
for (C.sub.22H.sub.26N.sub.8O.sub.2S) 466. found 467 [M+H]+. HPLC:
retention time: 15.36 min. purity: 100%.
Example 77
##STR00181##
[0422] Compound 7 (300 mg, 0.88 mmol) was reacted sequentially
sequentially with 5-methyl-1,3,4-thiadiazol-2-amine and
1-methylpiperazine using procedure similar to the preparation of
71. Compound 77 was obtained as white solid (70 mg, 15%). 1H NMR
(400 MHz, DMSO-d6) .delta. 11.83 (bs, 1H, NH), 10.54 (s, 1H, NH),
7.77-7.75 (m, 2H, Ar--H), 7.52 (d, J=8.4 Hz, 1H, Ar--H), 3.97-3.63
(m, 4H, 2CH.sub.2), 2.90-2.83 (m, 4H, 2CH.sub.2), 2.41 (s, 3H,
CH.sub.3), 1.87-1.81 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.21H.sub.25N.sub.9OS.sub.2) 483. found 484 [M+H]+. HPLC:
retention time: 13.07 min. purity: 94%.
Example 78
##STR00182##
[0424] Compound 7 (300 mg, 0.88 mmol) was reacted sequentially
sequentially with 3-methylisothiazol-5-amine and 1-methylpiperazine
using procedure similar to the preparation of 71. Compound 78 was
obtained as yellow solid (10 mg, 2%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.48 (bs, 1H, NH), 10.50 (s, 1H, NH), 7.70 (d, J=8.8 Hz,
1H, Ar--H), 7.50 (d, J=8.4 Hz, 1H, Ar--H), 6.69 (s, 1H, Ar--H),
4.76-4.32 (m, 2H, CH.sub.2), 4.58-4.37 (m, 2H, CH.sub.2), 3.11-3.00
(m, 2H, CH.sub.2), 2.76 (s, 3H, CH.sub.3), 2.28 (s, 3H, CH.sub.3),
2.87-2.81 (m, 1H, CH), 1.83-1.81 (m, 4H, Ar--H); ESI-MS: calcd for
(C.sub.22H.sub.26N.sub.8OS.sub.2) 482. found 483 [M+H]+. HPLC:
retention time: 15.39 min. purity: 99%.
Example 79
##STR00183##
[0426] Compound 5 (65 mg, 0.34 mmol) was reacted sequentially with
5-cyclopropyl-1H-pyrazol-3-amine and compound 65 using procedure
similar to the preparation of 71. Compound 79 was obtained as light
yellow solid (30 mg, 20%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.81
(s, 1H, NH), 10.07 (s, 2H, NH), 7.80-7.50 (m, 4H, Ar--H), 6.36 (s,
1H, Ar--H), 2.65-2.58 (m, 1H, CH), 1.85-1.80 (m, H, 1CH), 1.62-1.58
(m, 1H, CH), 1.11 (s, 3H, CH.sub.3), 1.09 (s, 3H, CH.sub.3),
0.99-0.44 (m, 8H, Ar--H); ESI-MS: calcd for
(C.sub.22H.sub.25N.sub.7OS) 436. found 436 [M+H]+. HPLC: retention
time: 28.99 min. purity: 95%.
Example 80
##STR00184##
[0428] To the 4-aminothiophenol (1.0 g, 7.98 mMol) in 30 mL of
CH.sub.2Cl.sub.2 at -10.degree. C. was added pyridine (966 .mu.L,
947 mg, 11.97 mMol) followed by dropwise addition of propionyl
chloride (690 .mu.L, 738 mg, 7.98 mMol). Reaction mixture was
stirred overnight to room temperature. Reaction mixture was washed
with 1N HCl and solvent was removed under reduced pressure. Crude
material was dissolved in 25 mL of MeOH and 10 mL of H.sub.2O.
K.sub.2CO.sub.3 (1.1 g, 7.98 mMol) was added and reaction mixture
was stirred at room temperature for 1 hr. After adjusting pH to 1
using 1N HCl, MeOH was evaporated and resulting aqueous solution
was extracted with CH.sub.2Cl.sub.2. Organic fractions were
combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered
and solvent was evaporated to give compound 80 as off-yellow solid
(980 mg, 68%). 1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40 (d, J=8.40
Hz, 2H), 7.24 (d, J=8.40 Hz, 2H), 7.11 (bs, 1H), 3.41 (s, 1H), 2.37
(q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H). MS (ESI) m/z 182
[M+H]+
Example 81
##STR00185##
[0430] Compound 5 (300 mg, 1.58 mmol) was reacted sequentially with
5-cyclopropyl-1H-pyrazol-3-amine and compound 80 using procedure
similar to the preparation of 71. Compound 81 was obtained as off
white solid (185 mg, 28%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.81
(s, 1H, NH), 10.10 (s, 2H, NH), 7.78-7.76 (m, 2H, Ar--H), 7.51 (d,
J=8.4 Hz, 1H, Ar--H), 6.36 (s, 1H, Ar--H), 2.36-2.31 (m, 2H,
CH.sub.2), 1.84-1.80 (m, 1H, CH), 1.65-1.56 (m, 1H, CH), 1.09 (t,
J=7.6 Hz, 3H, CH.sub.3), 0.99-0.45 (m, 8H, Ar--H); ESI-MS: calcd
for (C.sub.21H.sub.23N.sub.7OS) 421. found 422 [M+H]+. HPLC:
retention time: 25.92 min. purity: 99%.
Example 82
##STR00186##
[0432] Compound 5 (300 mg, 1.58 mmol) was reacted sequentially with
5-methyl-1H-pyrazol-3-amine and compound 80 using procedure similar
to the preparation of 71. Compound 82 was obtained as white solid
(200 mg, 32%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.82 (s, 1H, NH),
10.16 (s, 1H, NH), 10.09 (s, 1H, NH), 7.78-7.76 (m, 2H, Ar--H),
7.51 (d, J=8.4 Hz, 1H, Ar--H), 5.27 (s, 1H, Ar--H), 2.38-2.32 (m,
2H, CH.sub.2), 1.95 (s, 3H, CH.sub.3), 1.84-1.80 (m, 1H, CH), 1.10
(t, J=7.6 Hz, 3H, CH.sub.3), 0.97 (bs, 4H, Ar--H); ESI-MS: calcd
for (C.sub.19H.sub.21N.sub.7OS) 395. found 396 [M+H]+. HPLC:
retention time: 23.26 min. purity: 100%.
Example 83
##STR00187##
[0434] Compound 3 (300 mg, 1.69 mmol) was reacted sequentially with
5-methyl-1H-pyrazol-3-amine and compound 80 using procedure similar
to the preparation of 71. Compound 83 was obtained as white solid
(36 mg, 6%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.83 (s, 1H, NH),
10.20 (s, 1H, NH), 10.15 (s, 1H, NH), 7.77 (d, J=8.8 Hz, 2H,
Ar--H), 7.52 (d, J=8.8 Hz, 2H, Ar--H), 5.26 (s, 1H, Ar--H),
2.55-2.50 (m, 2H, CH.sub.2), 2.35 (dd, J=15.2 Hz, 2H, CH.sub.2),
1.94 (s, 3H, CH.sub.3), 1.18 (t, J=7.6 Hz, 3H, CH.sub.3), 1.10 (t,
J=7.6 Hz, 3H, CH.sub.3); ESI-MS: calcd for
(C.sub.18H.sub.21N.sub.7OS) 383. found 384 [M+H]+. HPLC: retention
time: 19.29 min. purity: 99%.
Example 84
##STR00188##
[0436] Compound 3 (100 mg, 0.56 mmol) was reacted sequentially with
5-cyclopropyl-1H-pyrazol-3-amine and compound 80 using procedure
similar to the preparation of 71. Compound 84 was obtained as off
white solid (150 mg, 65%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.82
(s, 1H, NH), 10.20 (s, 1H, NH), 10.12 (s, 1H, NH), 7.79 (d, J=8.4
Hz, 2H, Ar--H), 7.53 (d, J=8.4 Hz, 2H, Ar--H), 5.35 (s, 1H, Ar--H),
2.55-2.50 (m, 2H, CH.sub.2), 2.35 (dd, J=14.8 Hz, 2H, CH.sub.2),
1.62-1.60 (m, 1H, CH), 1.18 (t, J=7.2 Hz, 3H, CH.sub.3), 1.09 (t,
J=7.6 Hz, 3H, CH.sub.3), 0.78-0.76 (m, 2H, CH.sub.2), 0.45-0.44 (m,
2H, CH.sub.2); ESI-MS: calcd for (C.sub.20H.sub.23N.sub.7OS) 409.
found 410 [M+H]+. HPLC: retention time: 22.46 min. purity: 99%.
Example 85
##STR00189##
[0438] A solution of methylmagnesium bromide in ether (3M, 30 ml,
90 mmole) was added dropwise to a stirred solution of cyanuric
chloride (3.91 g, 21.20 mmole) in anhydrous dichloromethane at
-10.degree. C. After the addition was complete, the reaction
mixture was stirred at -5.degree. C. for 4 h, after which time
water was added dropwise at a rate such that the temperature of the
reaction stayed below 10.degree. C. After warming to room
temperature, the reaction mixture was diluted with additional water
and methylene chloride and passed through a pad of cilite. The
organic layer was dried and evaporated to give
2,4-dichloro-6-methyl-1,3,5-triazine of 85 as yellow solids (3.02
g, 87%). 1H NMR (CDCl.sub.3) .delta. 2.70 (s, 3H)
Example 86
##STR00190##
[0440] Compound 85 (300 mg, 1.82 mmol) was reacted sequentially
with 5-methyl-1H-pyrazol-3-amine and compound 80 using procedure
similar to the preparation of 71. Compound 86 was obtained as white
solid (350 mg, 52%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.84 (s,
1H, NH), 10.24 (s, 1H, NH), 10.16 (s, 1H, NH), 7.77 (d, J=8.4 Hz,
2H, Ar--H), 7.52 (dd, J=6.8 Hz, 2H, Ar--H), 5.25 (s, 1H, Ar--H),
2.36 (dd, J=14.8 Hz, 2H, CH.sub.2), 1.94 (s, 3H, CH.sub.3), 1.18
(t, J=7.6 Hz, 3H, CH.sub.3); ESI-MS: calcd for
(C.sub.18H.sub.21N.sub.7OS) 369. found 370 [M+H]+. HPLC: retention
time: 16.00 min. purity: 96%.
Example 87
##STR00191##
[0442] Compound 85 (300 mg, 1.82 mmol) was reacted sequentially
with 5-cyclopropyl-1H-pyrazol-3-amine and compound 80 using
procedure similar to the preparation of 71. Compound 87 was
obtained as off white solid (150 mg, 21%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.84 (s, 1H, NH), 10.22 (s, 1H, NH), 10.14 (s,
1H, NH), 7.78 (d, J=8.4 Hz, 2H, Ar--H), 7.52 (dd, J=8.4 Hz, 2H,
Ar--H), 5.34 (s, 1H, Ar--H), 2.33 (dd, J=15.2 Hz, 2H, CH.sub.2),
2.27 (s, 3H, CH.sub.3), 1.63-1.59 (m, 1H, CH), 1.08 (t, J=7.6 Hz,
3H, CH.sub.3), 0.78-0.76 (m, 2H, CH.sub.2), 0.45-0.44 (m, 2H,
CH.sub.2); ESI-MS: calcd for (C.sub.19H.sub.21N.sub.7OS) 395. found
396 [M+H]+. HPLC: retention time: 19.19 min. purity: 99%.
Example 88
##STR00192##
[0444] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of morpholine (204 mg, 2.35 mmol) and DIPEA (0.21 mL, 1.17
mmol) in THF (5 mL) was added to the above vial at room
temperature. The mixture was heated at 60.degree. C. for 0.5 h.
After cooling to room temperature, saturated NaHCO.sub.3 in water
was added to the flask and the mixture was extracted by
dichloromethane (3.times.25 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using DCM/MeOH, 0 to 5%
of Methanol in dichloromethane to provide compound 88 as white
solids (20 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.75 (br,
1H), 10.36 (s, 1H), 9.65 (br s, 1H), 7.69 (m, 2H), 7.48 (d, J=8.8
Hz, 2H), 5.23 (br s, 1H), 3.62-3.52 (m 8H), 2.14 (m, 3H), 1.78 (m,
1H), 0.78 (m, 4H); ESI-MS: calcd for
(C.sub.21H.sub.24N.sub.8O.sub.2S) 452. found 453 (MH+). HPLC:
retention time: 29.35 min. purity: 98%.
Example 89
##STR00193##
[0446] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of pyrrolidine (128 mg, 1.47 mmol) and DIPEA (0.21 mL,
1.17 mmol) in THF (5 mL) was added to the above vial at room
temperature. The mixture was heated at 60.degree. C. for 0.5 h.
After cooling to room temperature, saturated NaHCO.sub.3 in water
was added to the flask and the mixture was extracted by
dichloromethane (3.times.20 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using DCM/MeOH, 0 to 5%
of Methanol in dichloromethane to provide compound 89 as white
solids (76 mg, 30%). 1H NMR (400 MHz, DMSO-d6) .delta. 10.39 (br s,
1H), 9.50 (br s, 1H), 7.69 (m, 2H), 7.48 (d, J=8.8 Hz, 2H), 5.23
(br s, 1H), 3.55-3.12 (m 6H), 2.12 (m, 6H), 0.78 (m, 4H); ESI-MS:
calcd for (C.sub.21H.sub.24N.sub.8OS) 436. found 437 (MH+). HPLC:
retention time: 26.73 min. purity: 100%.
Example 90
##STR00194##
[0448] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of 3-morpholinopropan-1-amine (212 mg, 1.47 mmol) and
DIPEA (0.21 mL, 1.17 mmol) in THF (5 mL) was added to the above
vial at room temperature. The mixture was heated at 60.degree. C.
for 0.5 h. After cooling to room temperature, saturated NaHCO.sub.3
in water was added to the flask and the mixture was extracted by
dichloromethane (3.times.20 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using 0 to 7% of 7N
NH.sub.3 in Methanol/dichloromethane to provide compound 90 as
white solids (95 mg, 40%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.45
(br s, 1H), 10.39 (br s, 1H), 9.40 (br s, 1H), 7.69 (m, 2H), 7.48
(d, J=8.6 Hz, 2H), 5.23 (br s, 1H), 3.60-3.20 (m, 6H), 2.40-2.00
(m, 9H, 3.times.CH.sub.2+CH.sub.3), 1.80-1.20 (m, 3H), 0.78 (d,
J=8.0 Hz, 4H); ESI-MS: calcd for (C.sub.24H.sub.31N.sub.9O.sub.2S)
509. found 510 (MH+). HPLC: retention time: 11.21 min. purity:
92%.
Example 91
##STR00195##
[0450] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of N,N-dimethylethane-1,2-diamine (129 mg, 1.47 mmol) and
DIPEA (0.21 mL, 1.17 mmol) in THF (5 mL) was added to the above
vial at room temperature. The mixture was heated at 60.degree. C.
for 0.5 h. After cooling to room temperature, saturated NaHCO.sub.3
in water was added to the flask and the mixture was extracted by
dichloromethane (3.times.20 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using 0 to 7% of 7N
NH.sub.3 in Methanol/dichloromethane to provide compound 91 as
white solids (25 mg, 9.5%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.80
(br s, 1H), 10.45 (br s, 1H), 9.60 (br s, 1H), 7.69 (m, 2H), 7.48
(d, J=8.6 Hz, 2H), 5.23 (br s, 1H), 3.4 (brs, 6H), 2.80 (m, 4H),
2.20 (m, 3H), 1.80 (m, 1H), 0.78 (d, J=8.0 Hz, 4H); ESI-MS: calcd
for (C.sub.21H.sub.27N.sub.9OS) 453. found 454 (MH+). HPLC:
retention time: 10.16 min. purity: 95%.
Example 92
##STR00196##
[0452] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of N1,N1,N2-trimethylethane-1,2-diamine (150 mg, 1.47
mmol) and DIPEA (0.21 mL, 1.17 mmol) in THF (5 mL) was added to the
above vial at room temperature. The mixture was heated at
60.degree. C. for 0.5 h. After cooling to room temperature,
saturated NaHCO.sub.3 in water was added to the flask and the
mixture was extracted by dichloromethane (3.times.20 ml) and washed
by brine, dried over sodium sulfate and concentrated. The resulting
crude product was purified by Teledyne-Isco flash system by using
DCM/MeOH/TEA: (90/10/1) to provide compound 92 as white solids (25
mg, 9%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.90 (br s, 1H), 10.40
(br s, 1H), 9.60 (br s, 1H), 7.70 (m, 2H), 7.45 (d, J=8.6 Hz, 2H),
5.23 (br s, 1H), 3.80-1.99 (m, 16H), 1.80 (m, 1H), 0.78 (d, J=8.0
Hz, 4H); ESI-MS: calcd for (C.sub.22H.sub.29N.sub.9OS) 467. found
468 (MH+). HPLC: retention time: 13.08 min. purity: 84%.
Example 93
##STR00197##
[0454] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of n-butyl amine (107 mg, 1.47 mmol) and DIPEA (0.21 mL,
1.17 mmol) in THF (5 mL) was added to the above vial at room
temperature. The mixture was heated at 60.degree. C. for 0.5 h.
After cooling to room temperature, saturated NaHCO.sub.3 in water
was added to the flask and the mixture was extracted by
dichloromethane (3.times.20 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using DCM/MeOH: (95/5) to
provide compound 93 as white solids (22 mg, 8.5%). .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.90 (br s, 1H), 10.35 (br s, 1H), 9.60 (br
s, 1H), 7.70 (m, 2H), 7.45 (d, J=8.6 Hz, 2H), 5.3 (br s, 1H),
3.80-1.20 (m, 13H), 0.78 (d, J=8.0 Hz, 4H); ESI-MS: calcd for
(C.sub.21H.sub.26N.sub.8OS) 438. found 439 (MH+). HPLC: retention
time: 27.3 min. purity: 97%.
Example 94
##STR00198##
[0456] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of diethylamine (107 mg, 1.47 mmol) and DIPEA (0.21 mL,
1.17 mmol) in THF (5 mL) was added to the above vial at room
temperature. The mixture was heated at 60.degree. C. for 0.5 h.
After cooling to room temperature, saturated NaHCO.sub.3 in water
was added to the flask and the mixture was extracted by
dichloromethane (3.times.20 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using DCM/MeOH: (95/5) to
provide compound 94 as white solids (35 mg, 14%). 1H NMR (400 MHz,
DMSO-d6) .delta. 11.90 (br s, 1H), 10.38 (br s, 1H), 9.28 (br s,
1H), 7.70 (m, 2H), 7.45 (d, J=8.6 Hz, 2H), 5.28 (br s, 1H),
3.4-3.20 (m, 4H), 2.30 (m, 3H), 1.78 (m, 1H), 1.20 (m, 3H), 1.00
(m, 3H), 0.78 (m, 4H); ESI-MS: calcd for
(C.sub.21H.sub.26N.sub.8OS) 438. found 439 (MH+). HPLC: retention
time: 29.9 min. purity: 98%.
Example 95
##STR00199##
[0458] To a suspension of compound 2 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of cyclopropylamine (83 mg, 1.47 mmol) and DIPEA (0.21 mL,
1.17 mmol) in THF (5 mL) was added to the above vial at room
temperature. The mixture was heated at 60.degree. C. for 0.5 h.
After cooling to room temperature, saturated NaHCO.sub.3 in water
was added to the flask and the mixture was extracted by
dichloromethane (3.times.20 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using DCM/MeOH: (95/5) to
provide compound 95 as white solids (40 mg, 16%). ESI-MS: calcd for
(C.sub.20H.sub.22N.sub.8OS) 422. found 423 (MH+). HPLC: retention
time: 21.42 min. purity: 83%.
Example 96
##STR00200##
[0460] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. A
solution of 2-(piperazin-1-yl) ethanol (191 mg, 1.47 mmol) and
DIPEA (0.21 mL, 1.17 mmol) in THF (5 mL) was added to the above
vial at room temperature. The mixture was heated at 60.degree. C.
for 0.5 h. After cooling to room temperature, saturated NaHCO.sub.3
in water was added to the flask and the mixture was extracted by
dichloromethane (3.times.20 ml) and washed by brine, dried over
sodium sulfate and concentrated. The resulting crude product was
purified by Teledyne-Isco flash system by using DCM/MeOH: (90/10)
to provide compound 96 as white solids (45 mg, 15%). 1H NMR (400
MHz, DMSO-d6) .delta. 11.90 (br s, 1H), 10.38 (br s, 1H), 9.90 (br
s, 1H), 7.70 (m, 2H), 7.45 (d, J=8.6 Hz, 2H), 5.3 (br s, 1H), 4.40
(br s, 1H), 3.76-3.2 (br, 6H), 3.49 (m, 2H), 2.40-2.00 (m, 9H),
1.78 (m, 1H), 0.78 (d, J=8.0 Hz, 4H); ESI-MS: calcd for
(C.sub.23H.sub.29N.sub.9O.sub.2S) 495. found 496 (MH+). HPLC:
retention time: 21.42 min. purity: 99%.
Example 97
##STR00201##
[0462] To a suspension of compound 7 (0.2 g, 0.588 mmol) in THF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. Added
10 ml of THF, 5 ml of DMSO and 10 ml NH.sub.3OH to the above
reaction mixture and heated at 80.degree. C. for 20 min in
microwave. The resulting precipitate was filtered and washed with
cold water. The resulting solids were vacuum dried to provide
compound 97 as white solids (45 mg, 20%). 1H NMR (400 MHz, DMSO-d6)
.delta. 11.90 (br s, 1H), 10.38 (br s, 1H), 9.35 (br s, 1H), 7.70
(m, 2H), 7.45 (d, J=8.6 Hz, 2H), 6.95 (br s, 2H), 5.3 (br s, 1H),
4.40 (br s, 1H), 3.76-3.2 (br, 6H), 3.49 (m, 2H), 1.90 (br s, 3H)
(m, 9H), 1.78 (m, 1H), 0.78 (d, J=7.5.0 Hz, 4H); ESI-MS: calcd for
(C.sub.17H.sub.18N.sub.8OS) 382. found 383 (MH+). HPLC: retention
time: 14 min. purity: 81%.
Example 98
##STR00202##
[0464] To the cyanuric chloride (300 mg, 1.62 mMol) in 15 mL of THF
at -15.degree. C. was dropwise added thiol 80 (295 mg, 1.63 mMol)
and DIPEA (0.312 .mu.L, 1.79 mMol) in 10 mL of THF. Reaction
mixture was stirred for 90 minutes at -15.degree. C.
5-cyclopropyl-1H-pyrazol-3-amine was added (198 mg, 1.63 mMol)
followed by DIPEA (312 .mu.L, 1.79 mMol) and reaction mixture was
microwaved at 150.degree. C. for 10 minutes. 1-Methylpiparezine
(181 .mu.L, 1.63 mMol) and DIPEA (312 .mu.L, 1.79 mMol) was added
and reaction mixture was stirred for 36 h. 30 mL of EtOAC was added
and reaction mixture was washed with saturated NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4, filtered and solvent was removed under
reduced pressure. Flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10) afforded 152 mg (20%) of
desired product 98. 1H NMR (400 MHz, DMSO) .delta.11.25 (bs, 1H),
10.09 (s, 1H), 7.70 (m, 2H), 7.51 (m, 2H), 6.99 (bs, 1H), 3.90-3.50
(m, 4H), 2.45-2.21 (m, 9H), 2.19 (s, 3H), 1.09 (t, J=7.6 Hz, 3H).
MS (ESI) m/z 471 [M+H]+.
Example 99
##STR00203##
[0466] To the 4-mercaptobenzoic acid (318 mg of 90% acid, 1.85
mMol) in 10 mL of THF at 0.degree. C. was added DIPEA (645 .mu.L,
478 mg, 3.7 mMol) followed by dichloroethyltriazine (compound 3)
(300 mg, 1.69 mMol) in 5 mL of THF. Reaction mixture was stirred at
0.degree. C. for 30 minutes followed by 2 hours at room
temperature. Disappearance of starting material was confirmed by
TLC (CH.sub.2Cl.sub.2/MeOH 95/5). 5 mL of 1N HCl was added, organic
layer was separated and aqueous fraction was extracted with EtOAc
(3.times.50 mL). Organic fractions were combined, washed with
brine, dried over Na.sub.2SO.sub.4, filtered and solvent was
removed under reduced pressure. Flash column chromatography
(silica, CH.sub.2Cl.sub.2/MeOH 95/5) yielded 360 mg (72%) of 99 as
off-white solid. 1H NMR (400 MHz, CDCl.sub.3) .delta. 8.18 (d,
J=8.4 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 2.78 (q, J=7.2 Hz, 2H), 1.24
(t, J=7.2 Hz, 3H). MS (ESI) m/z 296 [M+H]+.
Example 100
##STR00204##
[0468] To the dichloroethyltriazine (compound 3) (4 g, 22.4 mMol)
in THF/Acetone/Water (200 mL/50 mL/50 mL) was added 5% aq.
NaHCO.sub.3 (40 mL) followed by 1-methylpiparezine (2.26 mL, 2.04
g, 20.4 mMol). Reaction mixture was stirred overnight at room
temperature. 200 mL of water was added, organic layer was separated
and aqueous layer was extracted with EtOAc (4.times.50 mL). Organic
fractions were combined, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was removed under reduced
pressure. After flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 95/5 0.1% TEA) fractions containing product
were combined, solvent was removed under reduced pressure to give
yellow oil that was re-dissolved in 20 mL of CH.sub.2Cl.sub.2 and
20 mL of MeOH and cooled to 0.degree. C. Addition of 2N HCl in
Et.sub.2O (20 mL, 40 mMol of HCl) followed by removal of solvent
under reduced pressure yielded 2.1 g (34%) of 100. 1H NMR (400 MHz,
DMSO) .delta. 3.47 (bs, 6H), 3.08 (bs, 2H), 2.77 (s, 3H), 2.65 (q,
J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz), 3H). MS (ESI) m/z 242
[M+H]+.
Example 101
##STR00205##
[0470] 5-methyl-1H-pyrazol-3-amine (526 mg, 5.42 mMol) and DIPEA
(942 .mu.L, 700 mg, 5.42 mMol) in 50 mL of THF was added dropwise
to the cyanuric chloride (1 g, 5.42 mMol) in 50 mL of THF at
-10.degree. C. After 30 minutes TLC confirmed disappearance of
starting material (CH.sub.2Cl.sub.2/MeOH 95/5). Reaction mixture
was warmed to 0.degree. C. followed by dropwise addition of
1-methylpiparezine (602 .mu.L, 543 mg, 5.42 mMol) and DIPEA (942
.mu.L, 700 mg, 5.42 mMol) in 50 mL of THF. After overnight stirring
at room temperature 150 mL of water was added, organic layer was
separated and aqueous layer was extracted with EtOAc (3.times.100
mL). Organic fractions were combined, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was removed under reduced
pressure. After flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 90/10 to 85/15 0.1% TEA) fractions containing
product were combined, solvent was removed under reduced pressure
to give white semi solid that was re-dissolved in 20 mL of
CH.sub.2Cl.sub.2 and 20 mL of MeOH and cooled to 0.degree. C.
Addition of 2N HCl in Et.sub.2O (5 mL, 10 mMol of HCl) followed by
removal of solvent under reduced pressure yielded 550 mg (30%) of
101. 1H NMR (400 MHz, CDCl.sub.3) .delta. 10.98 (bs, 1H), 10.22
(bs, 1H), 5.74 (s, 1H), 2.89 (bs, 4H), 2.18 (s, 3H), 1.93 (bs, 4H),
1.70 (s, 3H). MS (ESI) m/z 309 [M+H]+.
Example 102
##STR00206##
[0472] To the 5-methyl-1H-pyrazol-3-amine (86 mg, 0.86 mMol) in 2
mL of THF at 0.degree. C. was added DIPEA (165 .mu.L, 123 mg, 0.95
mMol). Reaction mixture was stirred at 0.degree. C. for 5 minutes
followed by addition of dichloroethyltriazine (compound 3) (200 mg,
1.12 mMol) in 1 mL of THF. Reaction mixture was stirred at
0.degree. C. for 2 hours. 25 mL of water was added, reaction
mixture was extracted with EtOAc (4.times.10 mL). Organic fractions
were combined, washed with brine, dried over Na.sub.2SO.sub.4,
filtered and solvent was removed over reduced pressure to yield 185
mg (90%) of unstable, crude pyrazoletriazine 102.
Example 103
##STR00207##
[0474] To the 1-methylpiperazine (55 .mu.L, 50 mg, 0.5 mMol) in 1
mL of THF at room temperature was added DIPEA (103 .mu.L, 76 mg,
0.59 mMol). Reaction mixture was stirred for 5 minutes at room
temperature and the pyrazoletriazine 102 (92 mg--crude, 0.39 mMol)
in 1 mL of THF was added at room temperature. Reaction mixture was
stirred for 3 days. 5 mL of water was added, reaction mixture was
extracted with EtOAc (3.times.5 mL). Organic fractions were
combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered
and solvent was evaporated. Column (silica, CH.sub.2Cl.sub.2/MeOH
97/3) yielded 80 mg (68%) of 103 as white solid. 1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.22 (s, 1H), 3.87 (bs, 4H), 2.59 (q, J=7.4 Hz,
2H), 2.43 (bs, 4H), 2.31 (s, 3H), 2.24 (s, 3H), 1.25 (t, J=7.4 Hz,
3H). MS (ESI) m/z 303 [M+H]+.
Example 104
##STR00208##
[0476] To the cyanuric chloride (300 mg, 1.63 mMol) in 15 mL of THF
at -10.degree. C. was dropwise added a solution of
5-methyl-1H-pyrazol-3-amine (158 mg, 1.63 mMol) and DIPEA (298
.mu.L, 221 mg, 1.71 mMol) in 10 mL of THF. Reaction mixture was
stirred for 30 minutes at -10.degree. C. 4-mercaptobenzoic acid
(280 mg of 90% acid, 1.63 mMol) in 10 mL of THF was added at
-10.degree. C. followed by DIPEA (596 .mu.L, 442 mg, 3.42 mMol).
Reaction mixture was stirred for 1 hour at 0.degree. C. and 3 hours
at room temperature. 1-methylpiparezine (181 .mu.L, 163 mg, 1.63
mMol) in 10 mL of THF was added at room temperature followed by
DIPEA (298 .mu.L, 221 mg, 1.71 mMol). After overnight stirring at
room temperature 100 mL of H.sub.2O was added, reaction mixture was
acidified with 2N HCl (0.8 mL, 1.6 mMol of HCl) and extracted with
CHCl.sub.3/i-PrOH (3/1) mixture (10.times.75 mL). Organic fractions
were combined and solvent was removed under reduced pressure. Flash
column chromatography (silica, CH.sub.2Cl.sub.2/MeOH/H.sub.2O
80/18/2) yielded 250 mg (36%) of 104 as a white solid. 1H NMR (400
MHz, DMSO) .delta. 9.68 (bs, 1H), 8.00 (bs, 2H), 7.25 (d, J=8.4 Hz,
2H), 6.15 (bs, 1H), 5.27 (s, 1H), 3.73 (bs, 4H), 2.48 (bs, 4H),
2.29 (s, 3H). MS (ESI) m/z 427 [M+H]+.
Example 105
##STR00209##
[0478] To the 5-methyl-1H-pyrazol-3-amine (66 mg, 0.68 mMol) in 2.5
mL of THF at room temperature was added DIPEA (261 .mu.L, 193 mg,
1.5 mMol). After 5 minutes, compound 99 (200 mg, 0.68 mMol) in 2.5
mL of THF was added. Reaction mixture was stirred at room
temperature for 2 days. 20 mL of H.sub.2O was added followed by 350
.mu.L of 2N HCl. Reaction mixture was extracted with EtOAc
(4.times.20 mL). Organic fractions were combined, washed with
brine, dried over Na.sub.2SO.sub.4, filtered and solvent was
removed under reduced pressure. Flash column chromatography (silica
CH.sub.2Cl.sub.2/MeOH/H.sub.2O 80/20/0 gradient to 80/18/2) yielded
top Rf product 105B (35 mg, 15%) 1H NMR (400 MHz, DMSO) .delta.
8.02 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 6.15 (s, 2H), 5.15
(s, 1H), 2.74 (q, J=7.6 Hz, 2H), 2.03 (s, 3H), 1.20 (t, J=7.2 Hz,
3H). MS (ESI) m/z 357 [M+H]+ and low Rf product 105A (55 mg, 23%).
1H NMR (400 MHz, DMSO) .delta. 10.27 (s, 1H), 8.03 (d, J=8.0 Hz,
2H), 7.70 (d, J=8.0 Hz, 2H), 5.21 (s, 1H), 2.55 (q, J=7.6 Hz, 2H),
1.94 (s, 3H), 1.18 (t, J=7.2 Hz, 3H). MS (ESI) m/z 357 [M+H]+.
Example 106
##STR00210##
[0480] To the carboxylic acid 104 (50 mg, 0.12 mMol) in 3 mL of DMF
at room temperature was added HBTU (55 mg, 0.14 mMol) followed by
DIPEA (52 .mu.L, 39 mg, 0.3 mMol). Reaction mixture was stirred at
room temperature for 5 minutes and cyclopropyl amine (21 .mu.L, 17
mg, 0.3 mMol) was added. After overnight stirring at room
temperature 30 mL of H.sub.2O was added and reaction mixture was
extracted with EtOAc (4.times.25 mL). Organic fractions were
combined, washed with water, brine, dried over Na.sub.2SO4,
filtered and solvent was removed under reduced pressure. Flash
column chromatography (silica, CH.sub.2Cl.sub.2/MeOH 85/15) yielded
106 as white solid (52 mg, 95%). 1H NMR (400 MHz, DMSO) .delta.
11.73 (bs, 1H), 9.56 (bs, 1H), 8.56 (bs, 1H), 7.92 (bs, 2H), 7.67
(d, J=8.8 Hz, 2H), 5.23 (s, 1H), 3.68 (bs, 4H), 2.85 (o, J=4 Hz,
1H), 2.32 (bs. 4H), 2.20 (s, 3H), 0.71 (m, 2H), 0.58 (m, 2H). MS
(ESI) m/z 466 [M+H]+.
Example 107
##STR00211##
[0482] To the carboxylic acid 105A (40 mg, 0.11 mMol) in 3 mL of
DMF at room temperature was added HBTU (49 mg, 0.13 mMol) followed
by DIPEA (49 .mu.L, 36 mg, 0.28 mMol). Reaction mixture was stirred
at room temperature for 5 minutes and cyclopropyl amine (20 .mu.L,
16 mg, 0.28 mMol) was added. After overnight stirring at room
temperature 30 mL of H.sub.2O was added and reaction mixture was
extracted with EtOAc (4.times.25 mL). Organic fractions were
combined, washed with water, brine, dried over Na.sub.2SO.sub.4,
filtered and solvent was removed under reduced pressure. Flash
column chromatography (silica, CH.sub.2Cl.sub.2/MeOH 95/5) yielded
107 as white solid (30 mg, 69%). 1H NMR (400 MHz, DMSO) .delta.
11.85 (bs, 1H), 10.26 (bs, 1H), 8.60 (bs, 1H), 7.97 (d, J=8.4 Hz,
2H), 7.71 (d, J=8.4 Hz, 2H), 5.16 (s, 1H), 2.86 (o, J=4 Hz, 1H), 2.
55 (q, J=7.6 Hz, 2H), 1.90 (s, 3H), 1.18 (t, J=7.6 Hz, 3H), 0.71
(m, 2H), 0.57 (m, 2H). MS (ESI) m/z 396 [M+H]+.
Example 108
##STR00212##
[0484] To the carboxylic acid 105B (30 mg, 0.084 mMol) and
cyclopropyl amine (15 .mu.L, 12 mg, 0.21 mMol) in 3 mL of DMF at
room temperature was added HBTU (38 mg, 0.1 mMol) followed by DIPEA
(37 .mu.L, 27 mg, 0.21 mMol). After overnight stirring at room
temperature 20 mL of H.sub.2O was added and reaction mixture was
extracted with EtOAc (4.times.25 mL). Organic fractions were
combined, washed with water, brine, dried over Na.sub.2SO.sub.4,
filtered and solvent was removed under reduced pressure. Flash
column chromatography (silica, CH.sub.2Cl.sub.2/MeOH 95/5) yielded
108 as white solid (4 mg, 12%). 1H NMR (400 MHz, DMSO) .delta. 7.79
(d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz), 6.26 (bs. 1H), 5.60 (s, 1H),
4.00 (bs. 2H), 2.94 (o, J=3.6 Hz, 1H), 2.83 (q, J=7.6 Hz, 2H), 2.00
(s, 3H), 1.29 (t, J=7.6 Hz, 3H), 0.89 (m, 2H), 0.66 (m, 2H). MS
(ESI) m/z 396 [M+H]+.
Example 109
##STR00213##
[0486] To the cyanuric chloride (300 mg, 1.63 mMol) in 15 mL of THF
at -20.degree. C. was dropwise added amide compound 80 (295 mg,
1.63 mMol) and DIPEA (312 mL, 232 mg, 1.79 mMol) in 10 mL of THF.
Reaction mixture was stirred at -20.degree. C. for 1 hr and
2-amino-5-methylthiazole (186 mg, 1.63 mMol) and DIPEA (312 .mu.L,
232 mg, 1.79 mMol) in 10 mL of THF was added dropwise. Reaction
mixture was warmed to 0.degree. C. and stirred for 3 hours at
0.degree. C. and 2 hours at room temperature. Methylpiperazine (181
.mu.L, 163 mg, 1.63 mMol) and DIPEA (312 .mu.L, 232 mg, 1.79 mMol)
in 10 mL of THF was added dropwise. Reaction mixture was stirred
overnight. 100 mL of H.sub.2O was added and reaction mixture was
extracted with EtOAc (3.times.) and CH.sub.2Cl.sub.2 (3.times.).
Organic layers were combined, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was evaporated to give crude
solid. Addition of a small amount of CH.sub.2Cl.sub.2 resulted in
formation of solid product that was filtered to give 80 mg (10%) of
desired triazine 109. 1H NMR (400 MHz, DMSO) .delta. 10.10 (bs,
1H), 8.97 (bs. 1H), 7.71 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H),
7.19 (s, 1H), 3.75-3.60 (m, 4H), 2.36 (q, J=7.6 Hz, 2H), 2.33 (m,
4H), 2.20 (s, 3H), 2.02 (d, J=1.6 Hz, 3H), 1.09 (t, J=7.6 Hz, 3H).
MS (ESI) m/z 236 [M+2H]2+, 471 [M+H]+.
Example 110
##STR00214##
[0488] To the cyclopropyldichlorotriazine (compound 5) (200 mg,
1.05 mMol) in 10 mL of THF at 0.degree. C. was dropwise added
2-amino-5-methylthiazole (120 mg, 1.05 mMol) and DIPEA (200 .mu.L,
148 mg, 1.15 mMol) in 10 mL of THF. Reaction mixture was stirred
for 3 hours at 0.degree. C., 2 hours at room temperature. Amide 80
(190 mg, 1.05 mMol) and DIPEA (200 .mu.L, 148 mg, 1.15 mMol) in 10
mL of THF was added and reaction mixture was stirred at 60.degree.
C. overnight. 50 mL of H.sub.2O was added, organic layer was
separated and aqueous layer was extracted with EtOAc. Combined
organic layers were washed with brine, dried over Na.sub.2SO.sub.4
and filtered. Removal of solvent yielded crude material. Addition
of small amount of CH.sub.2Cl.sub.2 resulted in formation of solid
product that was filtered to give 120 mg (28%) of compound 110. 1H
NMR (400 MHz, DMSO) .delta. 10.12 (bs, 1H), 9.03 (bs. 1H), 7.74 (d,
J=8.8 Hz, 2H), 7.52 (d, J=8.8 Hz, 2H), 7.13 (d, J=1.6 Hz, 1H), 2.36
(q, J=7.6 Hz, 2H), 2.03 (d, J=1.6 Hz, 3H), 2.01 (m, 1H), 1.20-1.00
(m, 4H), 1.10 (t, J=7.6 Hz, 3H). m/z 413 [M+H]+.
Example 111
##STR00215##
[0490] To the 4-aminothiophenol (1.0 g, 7.98 mMol) in 30 mL of
CH.sub.2Cl.sub.2 at -10.degree. C. was added pyridine (966 .mu.L,
947 mg, 11.97 mMol) followed by dropwise addition of benzoyl
chloride (930 .mu.L, 1.12 g, 7.98 mMol). Reaction mixture was
stirred overnight to room temperature. Reaction mixture was washed
with 1N HCl and solvent was removed under reduced pressure. Crude
material was dissolved in 25 mL of MeOH and 10 mL of H.sub.2O.
K.sub.2CO.sub.3 (1.1 g, 7.98 mMol) was added and reaction mixture
was stirred at room temperature for 1 hr. After adjusting pH to 1
using 1N HCl, MeOH was evaporated and resulting aqueous solution
was extracted with CH.sub.2Cl.sub.2. Organic fractions were
combined, washed with brine, dried over Na.sub.2SO.sub.4, filtered
and solvent was evaporated to give compound III as off-yellow solid
(940 mg, 51%). 1H NMR (400 MHz, CDCl.sub.3) .delta. 7.92-7.82 (m,
2H), 7.60-7.46 (m, 5H), 7.34-7.28 (m, 2H), 3.46 (s, 1H). MS (ESI)
m/z 230 [M+H]+.
Example 112
##STR00216##
[0492] To the cyanuric chloride (300 mg, 1.63 mMol) in 15 mL of THF
at -20.degree. C. was dropwise added amide 111 (374 mg, 1.63 mMol)
and DIPEA (312 .mu.L, 232 mg, 1.79 mMol) in 10 mL of THF. Reaction
mixture was stirred at -20.degree. C. for 1 hr, and
2-amino-5-methylthiazole (186 mg, 1.63 mMol) and DIPEA (312 .mu.L,
232 mg, 1.79 mMol) in 10 mL of THF was added dropwise. Reaction
mixture was warmed to 0.degree. C. and stirred for 3 hours at
0.degree. C. and 2 hours at room temperature. Methylpiperazine (181
.mu.L, 163 mg, 1.63 mMol) and DIPEA (312 .mu.L, 232 mg, 1.79 mMol)
in 10 mL of THF was added dropwise. Reaction mixture was stirred
overnight. 100 mL of H.sub.2O was added and reaction mixture was
extracted with EtOAc (3.times.) and CH.sub.2Cl.sub.2 (3.times.).
Organic layers were combined, washed with brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was evaporated to give crude
solid. Addition of a small amount of CH.sub.2Cl.sub.2 resulted in
formation of solid product 112 that was filtered to give 90 mg
(11%) of desired triazine. 1H NMR (400 MHz, DMSO) .delta. 10.47
(bs, 1H), 9.04 (bs. 1H), 7.95 (m, 4H), 7.56 (m, 5H), 7.20 (d, J=1.6
Hz, 1H), 3.78-3.60 (m, 4H), 2.38 (m, 4H), 2.20 (s, 3H), 2.03 (d,
J=1.6 Hz, 3H). MS (ESI) m/z 260 [M+2H]2+, 519 [M+H]+.
Example 113
##STR00217##
[0494] To the cyanuric chloride (300 mg, 1.62 mMol) in 10 mL of THF
at -15.degree. C. was dropwise added thiol 111 (374 mg, 1.63 mMol)
and DIPEA (312 .mu.L, 232 mg, 1.79 mMol) in 10 mL of THF. Reaction
mixture was stirred for 90 minutes at -15.degree. C.
2-amino-5-methylthiazole was added (186 mg, 1.63 mMol) followed by
DIPEA (312 .mu.L, 232 mg, 1.79 mMol) and reaction mixture was
microwaved at 150.degree. C. for 5 minutes. 1-Methylpiparezine (181
.mu.L, 163 mg, 1.63 mMol) and DIPEA (312 .mu.L, 232 mg, 1.79 mMol)
was added and reaction mixture was microwaved at 60.degree. C. for
15 minutes. 30 mL of EtOAC was added and reaction mixture was
washed with saturated NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was removed under reduced
pressure. Flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10) afforded 134 mg (16%) of
desired product 113. 1H NMR (400 MHz, DMSO) .delta.11.25 (bs, 1H),
10.46 (s, 1H), 7.95 (m, 4H), 7.57 (m, 5H), 6.99 (bs, 1H), 3.90-3.50
(m, 4H), 2.45-2.21 (m, 7H), 2.20 (s, 3H). MS (ESI) m/z 519
[M+H]+.
Example 114
##STR00218##
[0496] To the cyanuric chloride (300 mg, 1.62 mMol) in 10 mL of THF
at -15.degree. C. was dropwise added thiol 80 (295 mg, 1.63 mMol)
and DIPEA (312 .mu.L, 232 mg, 1.79 mMol) in 10 mL of THF. Reaction
mixture was stirred for 90 minutes at -15.degree. C.
2-amino-5-methylthiazole was added (186 mg, 1.63 mMol) followed by
DIPEA (312 .mu.L, 232 mg, 1.79 mMol) and reaction mixture was
microwaved at 150.degree. C. for 5 minutes. 1-Methylpiparezine (181
.mu.L, 163 mg, 1.63 mMol) and DIPEA (312 .mu.L, 232 mg, 1.79 mMol)
was added and reaction mixture was microwaved at 60.degree. C. for
15 minutes. 30 mL of EtOAC was added and reaction mixture was
washed with saturated NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was removed under reduced
pressure. Flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10) afforded 152 mg (20%) of
desired product 114. 1H NMR (400 MHz, DMSO) 811.25 (bs, 1H), 10.09
(s, 1H), 7.70 (m, 2H), 7.51 (m, 2H), 6.99 (bs, 1H), 3.90-3.50 (m,
4H), 2.45-2.21 (m, 9H), 2.19 (s, 3H), 1.09 (t, J=7.6 Hz, 3H). MS
(ESI) m/z 471 [M+H]+.
Example 115
##STR00219##
[0498] To the acid 104 (350 mg, 0.82 mMol) in 20 mL of DMF at room
temperature was added DIPEA (357 .mu.L, 265 mg, 2.05 mMol) and HBTU
(374 mg, 0.99 mMol). Reaction mixture was stirred at room
temperature for 120 minutes, and diisopropylamine (174 .mu.L, 121
mg, 2.05 mMol) was added. After overnight stirring, 50 mL of water
was added, and reaction mixture was extracted with EtOAc. Organic
fractions were combined, washed with water (2.times.), brine
(2.times.), dried over Na.sub.2SO.sub.4, filtered and solvent was
evaporated. Flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 95/95 to 85/15) yielded 220 mg (57%) of
desired amide compound 115. 1H NMR (400 MHz, DMSO) .delta. 11.73
(bs, 1H), 9.57 (bs, 1H), 8.34 (bs, 1H), 7.96 (bs, 2H), 7.67 (d,
J=7.2 Hz, 2H), 5.21 (s, 1H), 4.10 (h, J=6.8 Hz, 1H), 3.80-3.40 (m,
4H), 2.31 (m, 4H), 2.19 (s, 3H), 1.91 (s, 3H), 1.17 (d, J=6.8 Hz,
6H). MS (ESI) m/z 468 [M+H]+.
Example 116
##STR00220##
[0500] To the acid 104 (350 mg, 0.82 mMol) in 20 mL of DMF at room
temperature was added DIPEA (357 .mu.L, 265 mg, 2.05 mMol) and HBTU
(374 mg, 0.99 mMol). Reaction mixture was stirred at room
temperature for 120 minutes, and aniline (187 .mu.L, 191 mg, 2.05
mMol) was added. After overnight stirring, 50 mL of water was
added, and reaction mixture was extracted with EtOAc. Organic
fractions were combined, washed with water (2.times.), brine
(2.times.), dried over Na.sub.2SO.sub.4, filtered and solvent was
evaporated. Flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 95/95 to 85/15) yielded 151 mg (37%) of
desired amide compound 116. 1H NMR (400 MHz, DMSO) .delta. 11.74
(bs, 1H), 10.34 (bs, 1H), 9.58 (bs, 1H), 8.07 (bs, 2H), 7.76 (m,
4H), 7.37 (m, 2H), 7.12 (m, 1H), 5.31 (s, 1H), 3.80-3.40 (m, 4H),
2.31 (m, 4H), 2.19 (s, 3H), 1.94 (s, 3H). MS (ESI) m/z 502
[M+H]+.
Example 117
##STR00221##
[0502] To the compound 5 (300 mg, 1.58 mMol) in 10 mL of THF at
0.degree. C. was added 3-amino-5-methylpyrrazole (153 mg, 1.58
mMol) and DIPEA (303 .mu.L, 225 mg, 1.74 mMol) in 5 mL of THF.
Reaction mixture was stirred at 0.degree. C. for 2 hours.
4-aminobenzanilide (335 mg, 1.58 mMol) and DIPEA (303 .mu.L, 225
mg, 1.74 mmol) was added and reaction mixture was stirred at
60.degree. C. overnight. 30 mL of EtOAc was added and reaction
mixture was washed with saturated NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was evaporated. Flash column
chromatography (silica, CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10)
yielded 230 mg (34%) of desired product compound 117. 1H NMR (400
MHz, DMSO) .delta. 11.93 (s, 1H), 10.17 (s, 1H), 9.48 (bs, 2H),
8.00-7.45 (m, 9H), 6.36 (bs, 1H), 2.22 (s, 3H), 1.85 (m, 1H), 1.00
(m, 4H). MS (ESI) m/z 427 [M+H]+.
Example 118
##STR00222##
[0504] To the acid 104 (200 mg, 0.47 mMol) in 10 mL of DMF at room
temperature was added DIPEA (204 .mu.L, 151 mg, 1.17 mMol) and HBTU
(212 mg, 0.56 mMol). Reaction mixture was stirred at room
temperature for 120 minutes, and 4-fluoroaniline (132 .mu.L, 146
mg, 1.17 mMol) was added. After overnight stirring, 50 mL of water
was added, and reaction mixture was extracted with EtOAc. Organic
fractions were combined, washed with water (2.times.), brine
(2.times.), dried over Na.sub.2SO.sub.4, filtered and solvent was
evaporated. Flash column chromatography (silica,
CH.sub.2Cl.sub.2/MeOH 95/95 to 85/15) yielded 195 mg (78%) of
desired amide compound 118. 1H NMR (400 MHz, DMSO) .delta. 11.70
(bs, 1H), 9.56 (bs, 1H), 9.19 (s, 1H), 7.98 (bs, 2H), 7.70 (m, 2H),
7.37 (m, 2H), 7.13 (m, 2H), 5.23 (s, 1H), 4.47 (d, J=6.0 Hz, 2H),
3.80-3.60 (m, 4H), 2.30 (m, 4H), 2.19 (s, 3H), 1.77 (s, 3H). MS
(ESI) m/z 534 [M+H]+.
Example 119
##STR00223##
[0506] To the compound 5 (200 mg, 1.05 mMol) in 10 mL of THF at
0.degree. C. was added 3-amino-5-methylpyrrazole (102 mg, 1.05
mMol) and DIPEA (201 .mu.L, 150 mg, 1.15 mMol) in 5 mL of THF.
Reaction mixture was stirred at room temperature for 2 hours.
4-aminoacetanilide (158 mg, 1.05 mMol) and DIPEA (201 .mu.L, 150
mg, 1.15 mmol) was added and reaction mixture was stirred at
60.degree. C. overnight. 30 mL of EtOAc was added and reaction
mixture was washed with saturated NaHCO.sub.3, brine, dried over
Na.sub.2SO.sub.4, filtered and solvent was evaporated. Flash column
chromatography (silica, CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10)
yielded 60 mg (16%) of desired product compound 119. 1H NMR (400
MHz, DMSO) .delta. 11.92 (s, 1H), 9.81 (s, 1H), 9.40 (bs, 2H), 7.60
(bs, 2H), 7.48 (m, 2H), 6.36 (bs, 1H), 2.21 (s, 3H), 2.02 (s, 3H),
1.82 (m, 1H), 1.00 (m, 4H). MS (ESI) m/z 365 [M+H]+.
Example 120
##STR00224##
[0508] To the compound 7 (200 mg, 0.59 mMol) in 3 mL of DMF was
added 3-amino-5-methylisoxazole (58 mg, 0.59 mMol) and DIPEA (112
.mu.L, 83 mg, 0.65 mMol) in 1 mL of DMF. Reaction was stirred for 3
hours at room temperature. 1-methylpiparezine (66 .mu.L, 59 mg,
0.59 mMol) and DIPEA (112 .mu.L, 83 mg, 0.65 mMol) was added and
reaction was stirred overnight at room temperature. Added 10 mL of
water, reaction mixture was extracted with EtOAc. Organic fractions
were combined, washed with brine, dried over Na.sub.2SO.sub.4,
filtered and solvent was evaporated. Flash column chromatography
(silica, CH.sub.2Cl.sub.2/MeOH 98/2 to 95/5) yielded 57 mg (21%) of
desired product compound 120. 1H NMR (400 MHz, DMSO) .delta. 10.45
(s, 1H), 10.28 (s, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz,
2H), 5.75 (bs, 1H), 3.69 (bs, 4H), 2.31 (bs, 4H), 2.19 (s, 3H),
2.15 (s, 3H), 1.81 (p, J=6.4 Hz, 1H), 0.81 (m, 4H). MS (ESI) m/z
467 [M+H]+.
Example 121
##STR00225##
[0510] To the compound 7 (200 mg, 0.59 mMol) in 3 mL of DMF was
added 2-amino-4-methylpyridine (64 mg, 0.59 mMol) and DIPEA (112
.mu.L, 83 mg, 0.65 mMol) in 1 mL of DMF. Reaction was stirred for 3
hours at room temperature. 1-methylpiparezine (66 .mu.L, 59 mg,
0.59 mMol) and DIPEA (112 .mu.L, 83 mg, 0.65 mMol) was added and
reaction was stirred overnight at room temperature. Added 10 mL of
water, reaction mixture was extracted with EtOAc. Organic fractions
were combined, washed with brine, dried over Na.sub.2SO.sub.4,
filtered and solvent was evaporated. Flash column chromatography
(silica, CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10) yielded 5 mg (2%) of
desired product compound 121. 1H NMR (400 MHz, DMSO) .delta. 10.34
(s, 1H), 10.03 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 7.63 (m, 2H), 7.49
(m, 2H), 6.98 (d, J=5.2 Hz, 1H), 3.80-3.40 (bs, 4H), 2.36 (s, 3H),
2.30 (bs, 4H), 2.17 (s, 3H), 1.79 (m, 1H), 0.82 (m, 4H). MS (ESI)
m/z 478 [M+H]+.
Example 122
##STR00226##
[0512] To the compound 7 (200 mg, 0.59 mMol) in 3 mL of DMF was
added 2-amino-5-methylpicoline (63 mg, 0.59 mMol) and DIPEA (112
.mu.L, 83 mg, 0.65 mMol) in 1 mL of DMF. Reaction was stirred for 3
hours at room temperature. 1-methylpiparezine (66 .mu.L, 59 mg,
0.59 mMol) and DIPEA (112 .mu.L, 83 mg, 0.65 mMol) was added and
reaction was stirred overnight at room temperature. Added 10 mL of
water, reaction mixture was extracted with EtOAc. Organic fractions
were combined, washed with brine, dried over Na.sub.2SO.sub.4,
filtered and solvent was evaporated. Flash column chromatography
(silica, CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10) yielded 51 mg (20%)
of desired product compound 122. 1H NMR (400 MHz, DMSO) .delta.
10.46 (s, 1H), 9.51 (s, 1H), 8.02 (m, 1H), 7.70 (d, J=8.8 Hz, 2H),
7.51 (d, J=8.8 Hz, 2H), 7.35 (m, 1H), 7.20 (m, 1H), 3.63 (m, 4H),
2.29 (m, 4H), 2.19 (s, 3H), 2.16 (s, 3H), 1.85 (m, 1H), 0.86 (m,
4H). MS (ESI) m/z 477 [M+H]+.
Example 123
##STR00227##
[0514] To the compound 7 (200 mg, 0.59 mMol) in 3 mL of DMF was
added 2-amino-5-bromopyridine (102 mg, 0.59 mMol) and DIPEA (112
.mu.L, 83 mg, 0.65 mMol) in 1 mL of DMF. Reaction was stirred for 3
hours at room temperature. 1-methylpiparezine (66 .mu.L, 59 mg,
0.59 mMol) and DIPEA (112 .mu.L, 83 mg, 0.65 mMol) was added and
reaction was stirred overnight at room temperature. Added 10 mL of
water, reaction mixture was extracted with EtOAc. Organic fractions
were combined, washed with brine, dried over Na.sub.2SO.sub.4,
filtered and solvent was evaporated. Flash column chromatography
(silica, CH.sub.2Cl.sub.2/MeOH 98/2 to 95/5) yielded 54 mg (17%) of
desired product compound 123. 1H NMR (400 MHz, DMSO) .delta. 10.48
(s, 1H), 9.90 (s, 1H), 8.29 (m, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.52
(d, J=8.8 Hz, 2H), 7.45 (m, 1H), 7.40 (m, 1H), 3.80-3.55 (m, 4H),
2.31 (m, 4H), 2.19 (s, 3H), 2.16 (s, 3H), 1.85 (m, 1H), 0.88 (m,
4H). MS (ESI) m/z 541 and 543 [M+H]+.
Example 124
##STR00228##
[0516] To the compound 5 (200 mg, 1.05 mMol) in 5 mL of THF at room
temperature was added 3-amino-5-methylpyrazole (102 mg, 1.05 mMol)
and DIPEA (201 .mu.L, 150 mg, 1.15 mMol) in 5 mL of THF. Reaction
mixture was stirred at room temperature for 2 hours.
1,3-phenylenediamine (114 mg, 1.05 mMol) and DIPEA (201 .mu.L, 150
mg, 1.15 mMol) was added in 5 mL of THF, and reaction mixture was
stirred at 60.degree. C. overnight. 30 mL of EtOAc was added, and
reaction mixture was washed with saturated NaHCO.sub.3, brine,
dried over Na.sub.2SO.sub.4, filtered and solvent was evaporated.
Flash column chromatography (silica, CH.sub.2Cl.sub.2/MeOH 98/2 to
95/5 to 90/10) yielded 140 mg (74%) of desired product compound
124. 1H NMR (400 MHz, DMSO) .delta. 11.89 (s, 1H), 9.40 (s, 1H),
9.19 (s, 1H), 6.88 (s, 2H), 6.42 (s, 1H), 6.24 (s, 1H), 5.05 (s,
1H), 4.87 (s, 2H), 2.21 (s, 3H), 1.82 (m, 1H), 1.00 (m, 4H).
Example 125
##STR00229##
[0518] To the compound 3 (3 g, 16.9 mMol) in 10 mL of THF was
carefully added 3-amino-5-methylpyrazole (1.64 g, 16.9 mMol) and
DIPEA (3.24 mL, 2.41 g, 18.6 mMol) in 5 mL of THF. Reaction mixture
was stirred for 2 hours at room temperature. 1,4-phenylenediamine
(1.83 g, 16.9 mMol) and DIPEA (3.24 mL, 2.41 g, 18.6 mMol) was
added, and reaction was microwaved at 100.degree. C. for 60
minutes. Solvent was evaporated and flash column chromatography
(silica, CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10 0.1% Et.sub.3N)
yielded 2.7 g (51%) of desired product compound 125. 1H NMR (400
MHz, DMSO) .delta. 11.87 (s, 1H), 9.46 (s, 1H), 9.17 (s, 1H), 7.33
(m, 2H), 6.51 (d, J=8.4 Hz, 2H), 6.36 (bs, 1H), 4.82 (s, 2H), 2.47
(m, 2H), 2.20 (s, 3H), 1.20 (t, J=7.6 Hz, 3H). MS (ESI) m/z 311
[M+H]+.
Example 126
##STR00230##
[0520] To the compound 3 (3 g, 16.9 mMol) in 10 mL of THF was
carefully added 2-amino-5-methylthiazole (1.93 g, 16.9 mMol) and
DIPEA (3.24 mL, 2.41 g, 18.6 mMol) in 5 mL of THF. Reaction mixture
was stirred for 3 hours at room temperature. 1,4-phenylenediamine
(1.83 g, 16.9 mMol) and DIPEA (3.24 mL, 2.41 g, 18.6 mMol) was
added and reaction was microwaved at 150.degree. C. for 120
minutes. Solvent was evaporated and flash column chromatography
(silica, CH.sub.2Cl.sub.2/MeOH 95/5 to 90/10 0.1% Et.sub.3N)
yielded 1.9 g (34%) of desired product compound 126. 1H NMR (400
MHz, DMSO) .delta. 11.27 (s, 1H), 9.47 (s, 1H), 7.32 (m, 2H), 7.05
(s, 1H), 6.53 (d, J=8.4 Hz, 2H), 4.88 (s, 2H), 2.56 (q, J=7.2 Hz,
2H), 2.32 (s, 3H), 1.26 (m, 3H). MS (ESI) m/z 328 [M+H]+.
Example 127
##STR00231##
[0522] To a suspension of compound 2 (0.2 g, 0.588 mmol) in DMF (4
mL) was added DIPEA (0.13 mL, 0.65 mmol) and
3-amino-5-methylpyrazole (51 mg, 0.53 mmol). The mixture was heated
at 150.degree. C. for 15 minutes using microwave initiator. After
cooling to room temperature, saturated NaHCO.sub.3 in water was
added to the flask and the mixture was extracted by dichloromethane
(3.times.25 ml) and washed by brine, dried over sodium sulfate and
concentrated. The resulting crude product was purified by
Teledyne-Isco flash system by using DCM/MeOH, 0 to 5% of Methanol
in dichloromethane to provide compound 127 as white solids (20 mg,
7.5%). 1H NMR (400 MHz, DMSO-d6) .delta. 11.75 (br, 1H), 10.38 (s,
1H), 9.52 (br s, 1H), 7.65 (m, 2H), 7.48 (d, J=8.8 Hz, 2H), 5.33
(br s, 1H), 3.05 (s, 6H), 2.14 (m, 3H), 1.78 (m, 1H), 0.78 (m, 4H);
ESI-MS: calcd for (C.sub.19H.sub.22N.sub.8OS) 410. found 411 (MH+).
HPLC: retention time: 24.04 min. purity: 99%.
Example 128
[0523] This example illustrated Aurora Kinase Assays of selected
Compounds from this invention (referred to Daniele Fancelli et al,
J. Med. Chem., 2006, 49 (24), pp 7247-7251). The KinaseProfiler.TM.
Service Assay Protocols (Millipore) were used to test the kinase
inhibiting activity of novel compounds from this invention. To do
this, the buffer composition was as: 20 mM MOPS, 1 mM EDTA, 0.01%
Brij-35, 5% Glycerol, 0.1% .beta.-mercaptoethanol, 1 mg/mL BSA.
Test compounds were initially dissolved in DMSO at the desired
concentration, then serially diluted to the kinase assay buffer. In
a final reaction volume of 25 .mu.L, Aurora-A(h) (5-10 mU) is
incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 200 .mu.M LRRASLG
(Kemptide), 10 mM MgAcetate and [.gamma.33P-ATP]. The reaction was
initiated by the addition of the MgATP mix. After incubation for 40
minute at room temperature, the reaction was stopped by addition of
5 .mu.L of a 3% phosphoric acid solution. 10 .mu.L of the reaction
was then spotted onto a P30 filtermat and washed three times for 5
minutes in 50 mM phosphoric acid and once in methanol prior to
drying and scintillation counting. Wells containing substrate but
no kinase and wells containing a phosphopeptide control were used
to set 0% and 100% phosphorylation value, respectively.
[0524] Also Kinase Hotspot SM kinase assay was used to test the
compounds for IC.sub.50 or % inhibitions (Reaction Biology Corp.).
Inhibitor IC50 values were determined by titration of compound at
the optimal kinase concentration (Kinase EC50).
[0525] Table 1 shows representative data for the inhibition of
Aurora-A kinase by the compounds of this invention at a
concentration of 1 .mu.M.
TABLE-US-00001 TABLE 1 Example No. % Inhibition of aurora A @1
.mu.M 2 >90 4 >90 6 >90 8 <50 9 >50 10 >90 11
<50 12 >90 13 >50 16 <50 19 >90 20 >90 21 >90
30 >90 38 >90 39 >90 40 >50 41 <50 42 >50 44
>50 45 >50 47 <50 48 >50 49 >50 50 >90 52 >90
53 >90 54 >50 55 >90 56 >50 57 <50 58 <50 59
>50 60 <50 61 <50 63 <50 64 <50 66 <50 67 <50
69 <50 70 <50 71 >90 72 <50 73 >90 74 >90 75
<50 76 >50 77 <50 78 <50 79 >90 81 >90 82 >90
83 >90 84 >90 86 >90 87 >90 88 >90 89 >90 90
>90 91 >90 92 >50 93 >90 94 >90 96 >90 97 >90
98 >90 103 <50 106 >50 107 <50 108 <50 109 <50
110 >50 112 >50 113 >90 114 >90 115 >90 116 >90
117 >50 118 >90 119 >50 120 <50 121 <50 122 >50
123 >50 127 >90
[0526] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference were individually and
specifically indicated to be incorporated by reference and were set
forth in its entirety herein.
[0527] The use of the terms "a" and "an" and "the" and similar
referents in the context of describing the invention (especially in
the context of the following claims) are to be construed to cover
both the singular and the plural, unless otherwise indicated herein
or clearly contradicted by context. The terms "comprising,"
"having," "including," and "containing" are to be construed as
open-ended terms (i.e., meaning "including, but not limited to,")
unless otherwise noted. Recitation of ranges of values herein are
merely intended to serve as a shorthand method of referring
individually to each separate value falling within the range,
unless otherwise indicated herein, and each separate value is
incorporated into the specification as if it were individually
recited herein. All methods described herein can be performed in
any suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context. The use of any and all examples,
or exemplary language (e.g., "such as") provided herein, is
intended merely to better illuminate the invention and does not
pose a limitation on the scope of the invention unless otherwise
claimed. No language in the specification should be construed as
indicating any non-claimed element as essential to the practice of
the invention.
[0528] Preferred embodiments of this invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Variations of those preferred embodiments may
become apparent to those of ordinary skill in the art upon reading
the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than as specifically
described herein. Accordingly, this invention includes all
modifications and equivalents of the subject matter recited in the
claims appended hereto as permitted by applicable law. Moreover,
any combination of the above-described elements in all possible
variations thereof is encompassed by the invention unless otherwise
indicated herein or otherwise clearly contradicted by context.
* * * * *